Pyrazolo-pyridinone compounds and methods of use thereof

ABSTRACT

The present invention comprises a new class of compounds useful for the prophylaxis and treatment of protein kinase mediated diseases, including inflammation and related conditions. The compounds have a general Formula I 
     
       
         
         
             
             
         
       
     
     wherein A 1 , A 2 , A 3 , A 4 , B, R 1 , R 2 , R 3 , R 4  and R 5  are defined herein. The invention also comprises pharmaceutical compositions including one or more compounds of Formula I, uses of such compounds and compositions for treatment of P38 map kinase mediated diseases including rheumatoid arthritis, psoriasis, chronic obstructive pulmonary disease, pain and other inflammatory disorders, as well as intermediates and processes useful for the preparation of compounds of Formula I.

This application claims the benefit of U.S. Provisional Application No.60/928,155, filed May 7, 2007, U.S. Provisional Application No.61/066,424, filed Feb. 19, 2008 and U.S. Provisional Application No.61/043,089, filed Apr. 7, 2008 which are hereby incorporated byreference.

FIELD OF THE INVENTION

The invention relates generally to the field of pharmaceutical agentsand, more specifically, to pharmaceutically active compounds,pharmaceutical compositions and methods of use thereof, to treat variousdisorders, including TNF-α, IL-1β, IL-6 and/or IL-8 mediated diseasesand other maladies, such as inflammation and pain. The invention alsorelates to intermediates and processes useful in the preparation of suchcompounds.

BACKGROUND OF THE INVENTION

Protein kinases represent a large family of enzymes, which catalyze thephosphorylation of target protein substrates. The phosphorylation is atransfer reaction of a phosphate group from ATP to the proteinsubstrate. Common points of attachment for the phosphate group to theprotein substrate include, for example, a tyrosine, serine or threonineresidue. Protein tyrosine kinases (PTKs) are enzymes, which catalyze thephosphorylation of specific tyrosine residues in cellular proteins.Examples of kinases in the protein kinase family include, withoutlimitation, ab1, Akt, bcr-ab1, Blk, Brk, Btk, c-kit, c-Met, c-src,c-fins, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10,cRaf1, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, Erk, Fak, fes, FGFR1,FGFR2, FGFR3, FGFR4, FGFR5, Fgr, flt-1, Fps, Frk, Fyn, Hck, IGF-1R,INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, ros, tie,tie2, TRK, Yes, and Zap70. Due to their activity in numerous cellularprocesses, protein kinases have emerged as important therapeutictargets.

Protein kinases play a central role in the regulation and maintenance ofa wide variety of cellular processes and cellular function. For example,kinase activity acts as molecular switches regulating inflammatorycytokine production via various pathways. Uncontrolled or excessivecytokine production has been observed in many disease states, andparticularly in those related to inflammation.

The p38 protein kinase has been reported to be involved in theregulation of inflammatory cytokines. Interleukin-1 (IL-1) and TumorNecrosis Factor α (also referred to herein as TNF-α or TNF) arepro-inflammatory cytokines secreted by a variety of cells, includingmonocytes and macrophages, in response to many inflammatory stimuli(e.g., lipopolysaccharide (LPS)) or external cellular stress (e.g.,osmotic shock and peroxide).

Elevated levels of TNF-α over basal levels have been implicated inmediating or exacerbating a number of disease states includingrheumatoid arthritis (RA); osteoarthritis; rheumatoid spondylitis; goutyarthritis; inflammatory bowel disease (IBD); adult respiratory distresssyndrome (ARDS); psoriasis; Crohn's disease; allergic rhinitis;ulcerative colitis; anaphylaxis; contact dermatitis; asthma; muscledegeneration; cachexia; Reiter's syndrome; type II diabetes; boneresorption diseases; graft vs. host reaction; ischemia reperfusioninjury; atherosclerosis; brain trauma; multiple sclerosis; cerebralmalaria; sepsis; septic shock; toxic shock syndrome; fever, and myalgiasdue to infection. HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza,adenovirus, the herpes viruses (including HSV-1, HSV-2), and herpeszoster are also exacerbated by TNF-α.

TNF-α has been reported to play a role in head trauma, stroke, andischemia. For instance, in animal models of head trauma (rat), TNF-αlevels increased in the contused hemisphere (Shohami et al., J. Cereb.Blood Flow Metab. 14:615 (1994)). In a rat model of ischemia wherein themiddle cerebral artery was occluded, the levels of TNF-α mRNA of TNF-αincreased (Feurstein et al., Neurosci. Lett., 164:125 (1993)).Administration of TNF-α into the rat cortex has been reported to resultin significant neutrophil accumulation in capillaries and adherence insmall blood vessels. TNF-α promotes the infiltration of other cytokines(IL-1β, IL-6) and also chemokines, which promote neutrophil infiltrationinto the infarct area-(Feurstein, Stroke 25:1481 (1994)).

TNF-α appears to play a role in promoting certain viral life cycles anddisease states associated therewith. For instance, TNF-α secreted bymonocytes induced elevated levels of HIV expression in a chronicallyinfected T cell clone (Clouse et al., J. Immunol. 142:431 (1989)).Lahdevirta et al., (Am. J. Med. 85:289 (1988)) discussed the role ofTNF-α in the HIV associated states of cachexia and muscle degradation.

TNF-α is upstream in the cytokine cascade of inflammation. As a result,elevated levels of TNF-α may lead to elevated levels of otherinflammatory and proinflammatory cytokines, such as IL-1, IL-6, andIL-8. Elevated levels of IL-1 over basal levels have been implicated inmediating or exacerbating a number of disease states includingrheumatoid arthritis; osteoarthritis; rheumatoid spondylitis; goutyarthritis; inflammatory bowel disease; adult respiratory distresssyndrome (ARDS); psoriasis; Crohn's disease; ulcerative colitis;anaphylaxis; muscle degeneration; cachexia; Reiter's syndrome; type IIdiabetes; bone resorption diseases; ischemia reperfusion injury;atherosclerosis; brain trauma; multiple sclerosis; sepsis; septic shock;and toxic shock syndrome. Viruses sensitive to TNF-α inhibition, e.g.,HIV-1, HIV-2, HIV-3, are also affected by IL-1.

Antagonism of TNF-α has been reported to be beneficial for treatinguveitis (Reiff et al, A&R 44:141-145 (2001)); Sepsis (Abraham, Lancet,351:929 (1998)); Systemic Lupus Erythrematosis (SLE) (Aringer, A&R,50:3161 (2004)); Graft vs Host Disease (Couriel, Curr. Opinion Oncology,12:582 (2000)); Polymyositis and Dermatomyositis (Labiache,Rheumatology, 43:531 (2004)); Type II diabetes (Ruan, Cytokine GFReview, 14:447 (2003)); Sjogren's disease (Marriette, A&R, 50:1270(2004)), Sarcoidosis (Roberts, Chest, 124:2028 (2003)); Wegener'sgranulomatosis (WGET, New England J. Med., 352:351 (2005)) and post MIcardiac dysfunction (Sugano et al, Mol. Cell. Bioch., 266:127 (2004)).In addition, TNF-α has been reported to play a role in SAPHO, periodicfever, relapsing polychrondritis, multicentric reticulohistiocytosis,macrophage activation syndrome, Hyper IgD syndrome, familial Hibernianfever, Pyoderma gangrenosum, Cochleovestibular disorders, Cicatricalpemphigoid, Herniated intervertebral disc diseases, amyloidosis, CINCAsyndrome, myelodisplastic syndrome, alcoholic hepatitis, andendometriosis. Finally, indications which have already been approved fortreatment with a therapeutic agent which modulates TNF-α levels in theplasma, and/or other pro-inflammatory cytokines, include withoutlimitation, inflammatory bowel disease (IBD), psoriatis arthritis,ankylosing spondylitis and juvenile RA.

TNF-α and IL-1 appear to play a role in pancreatic β cell destructionand diabetes. Pancreatic β cells produce insulin which helps mediateblood glucose homeostasis. Deterioration of pancreatic β cells oftenaccompanies type I diabetes. Pancreatic β cell functional abnormalitiesmay occur in patients with type II diabetes. Type II diabetes ischaracterized by a functional resistance to insulin. Further, type IIdiabetes is also often accompanied by elevated levels of plasma glucagonand increased rates of hepatic glucose production. Glucagon is aregulatory hormone that attenuates liver gluconeogenesis inhibition byinsulin. Glucagon receptors have been found in the liver, kidney andadipose tissue. Thus, glucagon antagonists are useful for attenuatingplasma glucose levels (WO 97/16442, incorporated herein by reference inits entirety). By antagonizing the glucagon receptors, it is thoughtthat insulin responsiveness in the liver will improve, therebydecreasing gluconeogenesis and lowering the rate of hepatic glucoseproduction. Elevation of glucose levels along with the reducedexpression of IL-1Ra, an antagonist of IL-1 signaling, leads to impairedinsulin secretion, decreased cell proliferation and apoptosis. Inhibitonof IL-1 action has been shown to improve glycemia, b-cell secretoryfunction and reduce markers of systemic inflammation (Larsen, NewEngland J. Med., 356: 1517 (2007).

In rheumatoid arthritis models in animals, multiple intra-articularinjections of IL-1 led to an acute and destructive form of arthritis(Chandrasekhar et al., Clinical Immunol Immunopathol., 55:382 (1990)).In studies using cultured rheumatoid synovial cells, IL-1 is a morepotent inducer of stromelysin than is TNF-α (Firestein, Am. J. Pathol.,140:1309 (1992)). At sites of local injection, neutrophil, lymphocyte,and monocyte emigration has been observed. The emigration is attributedto the induction of chemokines (e.g., IL-8), and the up-regulation ofadhesion molecules (Dinarello, Eur. Cytokine Netw., 5:517-531 (1994)).

IL-1 also appears to play a role in promoting certain viral life cycles.For example, cytokine-induced increase of HIV expression in achronically infected macrophage line has been associated with aconcomitant and selective increase in IL-1 production (Folks et al., J.Immunol., 136:40 (1986)). Beutler et al. (J. Immunol., 135:3969 (1985))discussed the role of IL-1 in cachexia. Baracos et al. (New Eng. J.Med., 308:553 (1983)) discussed the role of IL-1 in muscle degeneration.

In rheumatoid arthritis (RA), both IL-1 and TNF-α induce synoviocytesand chondrocytes to produce collagenase and neutral proteases, whichleads to tissue destruction within the arthritic joints. In an in-vivoanimal model of arthritis, i.e., collagen-induced arthritis (CIA) inrats and mice, intra-articular administration of TNF-α either prior toor after the induction of CIA led to an accelerated onset of arthritisand a more severe course of the disease (Brahn et al., LymphokineCytokine Res. 11:253 (1992); and Cooper, Clin. Exp. Immunol., 898:244(1992)). IL-1 and TNF-α have been implicated in pro-inflammatorymechanisms in many human diseases including inflammatory arthritis,inflammatory bowel disease sepsis syndrome and both acute and cheonisinflammation of many organs. (Vassali P., The Pathophysiology of TumorNecrosis Factors, Ann. Rev. Immunology 10: 411-452 (1992) and DinarelloCalif., Biologic Basis for Interluekin-1 in disease, Blood, 87:2095-2147(1996)).

IL-6 also appears to play a role in, and therefore have applications to,pro-inflammatory and other malignant diseases. Particularly, deregulatedlevels of IL-6 are associated with various immunological diseases, suchas RA, systemic juvenile idiopathic arthritis (sJIA), polyarticular typeJIA, systemic lupus erythematosus (SLE), vasculitis syndrome, CastlemanDisease and Crohn's Disease; transplantation conditions such as acuterejection and graft-versus-host disease (GVHD); respiratory diseasessuch as interstitial pneumonia and bronchial; asthma; bone diseases suchas osteoporosis and Paget's disease, as well as various malignantdisease including multiple myeloma, renal cancer, prostate cancer,cardiac mixoma, Kaposis sarcoma, Mesothelioma, Malignant lymphoma, lungcancer and gastric cancer. (Nishimoto and Kishimoto, Review, 2: 619-625(2006)). It follows that the reduction and/or regulation of IL-6 levelsmay be useful for treatment of one or more of the above diseases.

IL-8 has been implicated in exacerbating and/or causing many diseasestates in which massive neutrophil infiltration into sites ofinflammation or injury (e.g., ischemia) is mediated by the chemotacticnature of IL-8, including, but not limited to, the following: asthma,inflammatory bowel disease, psoriasis, adult respiratory distresssyndrome, cardiac and renal reperfusion injury, thrombosis andglomerulonephritis. In addition to the chemotaxis effect on neutrophils,IL-8 also has the ability to activate neutrophils. Thus, reduction inIL-8 levels may lead to diminished neutrophil infiltration.

The role and activity of the p38 protein in RA and otherpro-inflammatory cytokine mediated diseases and conditions are becomingbetter understood. For example, Korb et al., Arthritis and Rheumatism,54: 2745-2756 (2006) describes the activation of the p38 alpha (p38α)and p38 gamma (p38γ) and the role which these two isoforms play in thedevelopment and progression of RA. Korb further describes thecorrelation between expression of p38 and the incidence of CRP in RA.Korb has found that the expression of these isoforms dominate inpatients with chronic inflammation and, therefore, concludes thateffective strategies to inhibit p38 kinase should aim to specificallytarget either or both of the isoforms. Medicherla et al., J.Pharmacology and Experimental Therapeutics, 318, 132-141 (2006) andNishikawa et al., Arthritis & Rheumatism, 48, 2670-2681 (2003) describeresults of an in-vivo collegan-induced arthritis (CIA) model in the ratand mouse. More specifically, they report that, in both animals,inhibition of p38α activity and related signaling improved clinicalscore and reversed bone and cartilage destruction. Ferrari,Cardiovascular Research 37:554 (1998) and Jacobsson et al., J Rheum.32:1213 (2005) describe how pro-inflammatory cytokines, such as TNF andIL-1, play a role in cadiovascular disease. More specifically, they havefound that blocking or reducing the levels of TNF-α have a protectiveeffect, and reduce the incidence of cardiovascular disease in RApatients. Behr et al., Circulation, 104, 1292 (2001) describes theability and efficacy of a p38 kinase inhibitor in treating hypertensivecardiac hypertrophy.

Several approaches have been taken to block the effect of TNF-α. Oneapproach involves using soluble receptors for TNF-α (e.g., TNFR-55 orTNFR-75), which have demonstrated efficacy in animal models ofTNF-α-mediated disease states. A second approach to neutralizing TNF-αusing a monoclonal antibody specific to TNF-α, cA2, has demonstratedimprovement in swollen joint count in a Phase II human trial ofrheumatoid arthritis (Feldmann et al., Immunological Reviews, pp.195-223-(1995)). These approaches block the effects of TNF-α and IL-1 byeither protein sequestration or receptor antagonism.

Yet another approach to block the effect of TNF-α, and otherpro-inflammatory cytokines, has been to modulate the activity of the p38kinase enzyme. For example, the PCT publication, WO 04/010995, publishedon Feb. 5, 2004, describes fused heteroaryl derivatives for use as p38kinase inhibitors in the treatment of I.A. and rheumatoid arthritis; PCTpublication, WO 2005/009937, published on Feb. 3, 2005, describes5-membered heterocycle-based p38 kinase inhibitors; U.S. Pat. No.6,635,644, issued Oct. 21, 2003, describes fused nitrogen-containingbicyclic ring systems as p38 inhibitors; and U.S. Pat. No. 6,794,380,issued Sep. 21, 2004, describes amide derivatives as p38 inhibitors.Despite the ongoing efforts, there needs to be effectiveanti-inflammatory agents which regulate the production ofpro-inflammatory cytokines, including TNF-α, IL-1β, IL-6 and/or IL-8.

BRIEF DESCRIPTION OF THE INVENTION

The present invention provides a new class of compounds useful in theprophylaxis and treatment of diseases mediated by pro-inflammatorycytokines, such as TNF-α, IL-1β, IL-6 and/or IL-8. The compounds,including stereoisomers, tautomers, solvates, pharmaceuticallyacceptable salts, derivatives or prodrugs thereof, are generally definedby Formula I

wherein A¹, A², A³, A⁴, B, R¹, R², R³, R⁴ and R⁵ are as described below.The invention also provides procedures for making compounds of FormulaI, compounds of Formula II, and intermediates useful in such procedures.

The compounds provided by the invention are capable of modulating thep38 kinase protein. To this end, the compounds of the invention areuseful for regulating the levels of pro-inflammatory cyclokines and fortherapeutic, prophylactic, acute and/or chronic treatment of TNF-α,IL-1β, IL-6 and/or IL-8 mediated diseases, such as those describedherein. For example, the compounds are useful for the prophylaxis andtreatment of RA, pain, and other conditions involving inflammation. Inanother embodiment, the invention provides pharmaceutical compositions,also commonly referred to as “medicaments”, comprising one or more ofthe compounds of the invention in combination with one or morepharmaceutically acceptable carrier(s) or excipient(s). Suchpharmaceutical compositions are useful to attenuate, alleviate, or treatp38 kinase-mediated disorders through inhibition of the activity of thep38 kinase enzyme.

The foregoing merely summarizes certain aspects of the invention and isnot intended, nor should it be construed, as limiting the invention inany way. All patents and other publications recited herein are herebyincorporated by reference in their entirety.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment of the invention, the compounds, includingstereoisomers, tautomers, solvates, pharmaceutically acceptable salts,derivatives or prodrugs thereof, are defined by general Formula I:

wherein

each of A¹, A², A¹ and A⁴, independently, is CR⁶ or N, provided that nomore than two of A¹, A², A³ and A⁴ is N;

B is O, S or N—CN;

R¹ is H, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl or C₃₋₁₀-cycloalkyl,each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyland C₄₋₁₀-cycloalkenyl optionally comprising 1-4 heteroatoms selectedfrom N, O and S and optionally substituted with one or more substituentsof R⁹,

or R¹ is a 3-8 membered monocyclic or 6-12 membered bicyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, saidheteroatoms selected from O, N, or S, wherein said ring system isoptionally substituted independently with one or more substituents ofR⁹;

each of R² and R³, independently, is H, halo, haloalkyl, NO₂, CN, OR⁷,SR⁷, NR⁷R⁷, NR⁷R⁸, C(O)R⁷, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl orC₃₋₁₀-cycloalkyl, each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl and C₄₋₁₀-cycloalkenyl optionally comprising 1-4heteroatoms selected from N, O and S and optionally substituted with oneor more substituents of R⁹;

R⁴ is CN, C(O)R⁷, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl orC₃₋₈-cycloalkyl, each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyland C₃₋₈-cycloalkyl optionally comprising 1-4 heteroatoms selected fromN, O and S and optionally substituted with one or more substituents ofR⁹;

R⁵ is R⁷, NR⁷R⁷, NR⁷R⁸, R⁷SR⁷, OR⁸, SR⁸, C(O)R⁷, C(NCN)R⁷, C(O)R⁸,C(NCN)R⁸, C(O)C(O)R⁷, OC(O)R⁷, COOR⁸, C(O)C(O)R⁸, OC(O)R⁸, COOR⁸,C(O)NR⁷R⁷, C(O)NR⁷R⁸, OC(O)NR⁷R⁸, NR⁷C(O)R⁷, NR⁷C(O)R⁸, NR⁷C(O)NR⁷R⁷,NR⁷C(O)NR⁷R⁸, NR⁷(COOR⁷), NR⁷(COOR⁸), S(O)₂R⁷, S(O)₂R⁸, S(O)NR⁷R⁷,S(O)₂NR⁷R⁸, NR⁷S(O)₂NR⁷R⁸, NR⁷S(O)R⁷ or NR⁷S(O)₂R⁸;

each R⁶, independently, is H, halo, haloalkyl, NO₂, CN, OR¹, NR⁷R⁷ orC₁₋₁₀-alkyl, the C₁₋₁₀-alkyl optionally comprising 14 heteroatomsselected from N, O and S and optionally substituted with one or moresubstituents of R⁹;

each R⁷, independently, is H, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl or C₄₋₁₀-cycloalkenyl, each of the C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl and C₄₋₁₀-cycloalkenyloptionally comprising 1-4 heteroatoms selected from N, O and S andoptionally substituted with one or more substituents of NR⁸R⁹, NR⁹R⁹,OR⁸, SR⁸, OR⁹, SR⁹, C(O)R⁸, OC(O)R⁹, COOR⁹, C(O)R⁹, OC(O)R⁹, COOR⁹,C(O)NR⁸R⁹, C(O)NR⁹R⁹, NR⁹C(O)R⁸, NR⁹C(O)R⁹, NR⁹C(O)NR⁸R⁹, NR⁹C(O)NR⁹R⁹,NR⁹(COOR⁸), NR⁹(COOR⁹), OC(O)NR⁸R⁹, OC(O)NR⁹R⁹, S(O)₂R⁸, S(O)₂NR⁸R⁹,S(O)₂R⁹, S(O)₂NR⁹R⁹, NR⁹S(O)₂NR⁸R⁹, NR⁹S(O)₂NR⁹R⁹, NR⁹S(O)₂R⁸,NR⁹S(O)₂R⁹, R⁸ or R⁹;

R⁸ is a partially or fully saturated or fully unsaturated 3-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, andwherein each ring of said ring system is optionally substitutedindependently with 1-5 substituents of R⁹, oxo, NR⁹R⁹, OR⁹, SR⁹, C(O)R⁹,COOR⁹, C(O)NR⁹R⁹, NR⁹C(O)R⁹, NR⁹C(O)NR⁹R⁹, OC(O)NR⁹R⁹, S(O)₂R⁹,S(O)₂NR⁹R⁹, NR⁹S(O)₂R⁹, or a partially or fully saturated or unsaturated5-6 membered ring of carbon atoms optionally including 1-3 heteroatomsselected from O, N, or S, and optionally substituted independently with1-3 substituents of R⁹;

alternatively, R⁷ and R⁸ taken together form a saturated or partially orfully unsaturated 0.5-6 membered monocyclic or 7-10 membered bicyclicring of carbon atoms optionally including 1-3 heteroatoms selected fromO, N, or S, and the ring optionally substituted independently with 1-5substituents of R⁹; and

R⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, oxo, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxylor a saturated or partially or fully unsaturated 5-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S,wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and each ring ofsaid ring system is optionally substituted independently with 1-3substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl.

In another embodiment, the compounds of Formula I include compoundswherein A¹ is CR⁶, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I include compoundswherein A² is CR⁶, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I include compoundswherein A³ is CR⁶, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I include compoundswherein A⁴ is CR⁶, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I include compoundswherein A¹ is N, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I include compoundswherein A² is N, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I include compoundswherein A³ is N, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I include compoundswherein A⁴ is N, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I include compoundswherein each of A¹, A², A³ and A⁴, independently, as CR⁶, in conjunctionwith any of the above or below embodiments.

In another embodiment, the compounds of Formula I include compoundswherein three of A¹, A², A³ and A⁴, independently, is CR⁶ and the otherone of A¹, A², A³ and A⁴, independently, as N, in conjunction with anyof the above or below embodiments.

In another embodiment, the compounds of Formula I include compoundswherein two of A¹, A², A³ and A⁴, independently, is CR⁶ and the othertwo of A¹, A², A³ and A⁴, independently, as N, in conjunction with anyof the above or below embodiments.

In another embodiment, the compounds of Formula I include compoundswherein two of A¹, A², A³ and A⁴, independently, is CR⁶ and the othertwo of A¹, A², A¹ and A⁴, independently, as CH, in conjunction with anyof the above or below embodiments.

In another embodiment, the compounds of Formula I include compoundswherein each of A¹ and A², independently, is CR⁶ and each of A³ and A⁴,independently, is CH, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I include compoundswherein each of A¹ and A², independently, is CR⁶ wherein each R⁶,independently, is HI F, Cl, Br, CF₃, —OCF₃, C₂F₅, —OC₂F₅, —O—C₁₋₄-alkyl,—C₁₋₄-alkyl-O—C₁₋₆-alkyl, —S—C₁₋₄-alkyl, —C₁₋₄-alkyl-S—C₁₋₆-alkyl,—NH—C₁₋₆-alkyl, —N(C₁₋₆-alkyl)₂, —C₁₋₄-alkyl-NH—C₁₋₄-alkyl,—C₁₋₃-alkyl-N(C₁₋₄-alkyl)₂, NO₂, NH₂, CN or C₁₋₁₀-alkyl, and each of A³and A⁴, independently, is CH, in conjunction with any of the above orbelow embodiments.

In another embodiment, the compounds of Formula I include compoundswherein each of A¹ and A², independently, is CR⁶ wherein each R⁶,independently, is H, F, Cl, Br, CF₃, —OCF₃, C₂F₅, —OC₂F₅, —O—C₁₋₄-alkyl,—S—C₁₋₄-alkyl, —NH—C₁₋₄-alkyl, OH, NO₂, NH₂, CN, methyl, ethyl orpropyl, and each of A³ and A⁴, independently, is CH, in conjunction withany of the above or below embodiments.

In another embodiment, the compounds of Formula I include compoundswherein each of A¹, A², A³ and A⁴, independently, is CR⁶ and each R⁶,independently, is H, F, Cl, Br, CF₃, —OCF₃, C₂F₅; —OC₂F₅, —O—C₁₋₆-alkyl,—C₁₋₄-alkyl-O—C₁₋₆-alkyl, —S—C₁₋₄-alkyl, —C₁₋₄-alkyl-S—C₁₋₆-alkyl,—NH—C₁₋₆-alkyl, —N(C₁₋₄-alkyl)₂, —C₁₋₄-alkyl-NH—C₁₋₄-alkyl,—C₁₋₃-alkyl-N(C₁₋₄-alkyl)₂, NO₂, NH₂, CN or C₁₋₁₀-alkyl, in conjunctionwith any of the above or below embodiments.

In another embodiment, the compounds of Formula I include compoundswherein each of A¹, A², A³ and A⁴, independently, is CR⁶ wherein eachR⁶, independently, is H, F, Cl, Br, CF₃, —OCF₃, C₂F₅, —OC₂F₅,—O—C₁₋₆-alkyl, —C₁₋₄-alkyl-O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl,—C₁₋₄-alkyl-S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl, —N(C₁₋₆-alkyl)₂,—C₁₋₄-alkyl-NH—C₁₋₆-alkyl, —C₁₋₃-alkyl-N(C₁₋₄-alkyl)₂, NO₂, NH₂, CN,C₁₋₁₀-alkyl, the C₁₋₁₀-alkyl optionally substituted with one or moresubstituents of R⁹; and each of R² and A³, independently, is H or halo,in conjunction with any of the above or below embodiments.

In another embodiment, related to the immediately preceedingembodiments, the compounds of Formula I include compounds wherein eachR⁶, independently, is H, halo, haloalkyl, NO₂, CN, OR⁷, NR⁷R⁷ orC₁₋₁₀-alkyl, the C₁₋₁₀-alkyl optionally comprising 1-4 heteroatomsselected from N, O and S and optionally substituted with one or moresubstituents of R⁹, in conjunction with any of the above or belowembodiments.

In another embodiment, related to the immediately preceedingembodiments, Formula I includes compounds wherein each R⁶,independently, is H, F, Cl, Br, CF₃, —OCF₃, C₂F₅, —OC₂F₅, —O—C₁₋₄-alkyl,—C₁₋₄-alkyl-O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl, —C₁₋₄-alkyl-S—C₁₋₆-alkyl,—NH—C₁₋₄-alkyl, —N(C₁₋₆-alkyl)₂, —C₁₋₄-alkyl-NH—C₁₋₄-alkyl,—C₁₋₃-alkyl-N(C₁₋₄-alkyl)₂, NO₂, NH₂, CN, C₁₋₁₀-alkyl or the C₁₋₁₀-alkyloptionally substituted with one or more substituents of R⁹, inconjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include compoundswherein one of A¹, A², A³ and A⁴, independently, is N and the remainingof A¹, A², A³ and A⁴, independently, is CR⁶ wherein each R⁶,independently, is H, F, Cl, Br, CF₃, —OCF₃, C₂F₅, —OC₂F₅, —O—C₁₋₆-alkyl,—C₁₋₄-alkyl-O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl, —C₁₋₄-alkyl-S—C₁₋₆-alkyl,—NH—C₁₋₆-alkyl, —N(C₁₋₆-alkyl)₂, —C₁₋₄-alkyl-NH—C₁₋₆-alkyl,—C₁₋₃-alkyl-N(C₁₋₄-alkyl)₂, NO₂, NH₂, CN, C₁₋₁₀-alkyl, the C₁₋₁₀-alkyloptionally substituted with one or more substituents of R⁹, inconjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formulas I include compoundswherein B is O, S or N—CN, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formulas I include compoundswherein B is O, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formulas I include compoundswherein B is S, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formulas I include compoundswherein B is N—CN, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formulas I include compoundswherein B is O or S, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I includes compoundswherein R¹ is H, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl orC₃₋₁₀-cycloalkyl, each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl and C₄₋₁₀-cycloalkenyl optionally comprising 14heteroatoms selected from N, O and S and optionally substituted with oneor more substituents of R⁹, in conjunction with any of the above orbelow embodiments.

In another embodiment, the compounds of Formula I includes compoundswherein R¹ is C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl orC₃₋₁₀-cycloalkyl, each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl and C₄₋₁₀-cycloalkenyl optionally comprising 14heteroatoms selected from N, O and S and optionally substituted with oneor more substituents of R⁹, in conjunction with any of the above orbelow embodiments.

In another embodiment, the compounds of Formula I includes compoundswherein R¹ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, pentyl, neopenyl, hexyl, cyclopropyl, cyclopentyl, cyclohexylor alkyl, each of which is optionally comprising 14 heteroatoms selectedfrom N, O and S and optionally substituted with one or more substituentsof R⁹, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I includes compoundswherein R¹ is a 3-8 membered monocyclic or 6-12 membered bicyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, saidheteroatoms selected from O, N, or S, wherein said ring system isoptionally substituted independently with one or more substituents ofR⁹, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I includes compoundswherein R¹ is phenyl, naphthyl, pyridyl, pyrimidyl, triazinyl,quinolinyl, isoquinolinyl, quinazolinyl, isoquinazolinyl, thiophenyl,furyl, tetrahydrofuryl, pyrrolyl, tetrahydropyrrolyl, pyrazolyl,imidazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, oxazolinyl,isoxazolyl, isoxazolinyl, oxadiazolyl, isothiazolyl, indolyl, indolinyl,isoindolyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl,benzisoxazolyl, benzopyrazolyl, benzothiazolyl, benzimidazolyl,piperidinyl, pyranyl, cyclopropyl, cyclobutyl or cyclohexyl, each ofwhich is optionally substituted independently with one or moresubstituents of R⁹, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I includes compoundswherein R¹ is phenyl, pyridyl, pyrimidyl, triazinyl, pyridazinyl,pyrazinyl, thiophenyl, furyl, tetrahydrofuryl, pyrrolyl,tetrahydropyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl,thiazolyl, oxazolyl, oxazolinyl, isoxazolyl, isoxazolinyl, oxadiazolyl,isothiazolyl, piperidinyl, pyranyl, cyclopropyl, cyclobutyl orcyclohexyl, each of which is optionally substituted independently withone or more substituents of R⁹, in conjunction with any of the above orbelow embodiments.

In another embodiment, the compounds of Formula I includes compoundswherein R¹ is phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl,thiophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl,thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl or isothiazolyl, each ofwhich is optionally substituted independently with one or moresubstituents of R⁹, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I includes compoundswherein R¹ is phenyl, pyridyl, pyrimidyl, pyridazinyl or pyrazinyl, eachof which is optionally substituted independently with one or moresubstituents of R⁹, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I includes compoundswherein R¹ is piperidinyl, pyranyl, cyclopropyl, cyclobutyl orcyclohexyl, each of which is optionally substituted independently withone or more substituents of R⁹, in conjunction with any of the above orbelow embodiments.

In another embodiment, the compounds of Formula I includes compoundswherein R¹ is phenyl or pyridyl, each of which is optionally substitutedindependently with one or more substituents of R⁹, in conjunction withany of the above or below embodiments.

In another embodiment, the compounds of Formula I includes compoundswherein R¹ is phenyl, optionally substituted independently with one ormore substituents of R⁹, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I includes compoundswherein R¹ is thiophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl,triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl or isothiazolyl,each of which is optionally substituted independently with one or moresubstituents of R⁹, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I includes compoundswherein R² is H, halo, haloalkyl, NO₂, CN, OR⁷, SR⁷, NR⁷R⁷, NR⁷R⁸,C(O)R⁷, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl or C₃₋₁₀-cycloalkyl,each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyland C₄₋₁₀-cycloalkenyl optionally comprising 1-4 heteroatoms selectedfrom N, O and S and optionally substituted with one or more substituentsof R⁹, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I includes compoundswherein R² is H, halo, haloalkyl, NO₂, CN, OR⁷, NR⁷R⁷ or C₁₋₁₀-alkyl, inconjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I includes compoundswherein R² is H, halo, haloalkyl or C₁₋₁₀-alkyl, in conjunction with anyof the above or below embodiments.

In another embodiment, the compounds of Formula I includes compoundswherein R² is H, halo, methyl or ethyl, in conjunction with any of theabove or below embodiments.

In another embodiment, the compounds of Formula I includes compoundswherein R² is H, F, Cl, methyl or ethyl, in conjunction with any of theabove or below embodiments.

In another embodiment, the compounds of Formula I includes compoundswherein R² is H, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I includes compoundswherein R³ is H, halo, haloalkyl, NO₂, CN, OR⁷, SR⁷, NR⁷R⁸, NR⁷R⁸,C(O)R⁷, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl or C₃₋₁₀-cycloalkyl,each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyland C₄₋₁₀-cycloalkenyl optionally comprising 14 heteroatoms selectedfrom N, O and S and optionally substituted with one or more substituentsof R⁹, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I includes compoundswherein R³ is H, halo, haloalkyl, NO₂, CN, OR⁷, NR⁷R⁷ or C₁₋₁₀-alkyl, inconjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I includes compoundswherein R³ is H, halo, haloalkyl or C₁₋₁₀-alkyl, in conjunction with anyof the above or below embodiments.

In another embodiment, the compounds of Formula I includes compoundswherein R³ is H, halo, methyl or ethyl, in conjunction with any of theabove or below embodiments.

In another embodiment, the compounds of Formula I includes compoundswherein R³ is H, F, Cl, methyl or ethyl, in conjunction with any of theabove or below embodiments.

In another embodiment, the compounds of Formula I includes compoundswherein R³ is H, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I includes compoundswherein each of R² and R³, independently, is H or halo, in conjunctionwith any of the above or below embodiments.

In another embodiment, the compounds of Formula I includes compoundswherein each of R² and R³, independently, is H, F, Cl, methyl or ethyl,in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I includes compoundswherein each of R² and R³, independently, is H or F, in conjunction withany of the above or below embodiments.

In another embodiment, the compounds of Formula I includes compoundswherein each of R² and R³, independently, is H, in conjunction with anyof the above or below embodiments.

In another embodiment, the compounds of Formula I includes compoundswherein R⁴ is CN, C(O)R⁷, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl or C₂₋₁₀-alkynyl,each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl and C₂₋₁₀-alkynyl optionallycomprising 14 heteroatoms selected from N, O and S and optionallysubstituted with one or more substituents of R⁹, in conjunction with anyof the above or below embodiments.

In another embodiment, the compounds of Formula I includes compoundswherein R⁴ is CN, C(O)R⁷, C₁₋₄-alkylC(O)R⁷, methyl, ethyl, propyl,isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentylor C₁₋₄-alkyl-amino-C₁₋₄-alkyl or C₁₋₁₀-dialkylaminoC₁₋₄-alkyl-, inconjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I includes compoundswherein R⁴ is methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl,isobutyl, tert-butyl, pentyl or neopentyl, in conjunction with any ofthe above or below embodiments.

In another embodiment, the compounds of Formula I includes compoundswherein R⁵ is R⁷, NR⁷R⁷, NR⁷R⁸, OR⁷, SR⁷, OR⁸, SR⁸, C(O)R⁷, C(NCN)R⁷,C(O)R⁸, C(NCN)R⁸, C(O)C(O)R⁷, OC(O)R⁷, COOR⁷, C(O)C(O)R⁸, OC(O)R⁸,COOR⁸, C(O)NR⁷R⁷, C(O)NR⁷R⁸, OC(O)NR⁷R⁸, NR⁷C(O)R⁷, NR⁷C(O)R⁸,NR⁷C(O)NR⁷R⁷, NR⁷C(O)NR⁷R⁸, NR⁷(COOR⁷), NR⁷(COOR⁸), S(O)₂R⁷, S(O)₂R⁸,S(O)₂NR⁷R⁷, S(O)₂NR⁷R⁸, NR⁷S(O)₂NR⁷R⁸, NR⁷S(O)₂R⁷ or NR⁷S(O)₂R⁸, inconjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I includes compoundswherein R⁵ is NR⁷R⁷, NR⁷R⁸, C(O)R⁷, C(O)R⁸, C(O)NR⁷R⁷, C(O)NR⁷R⁸,NR⁷C(O)R⁷, NR⁷C(O)R⁸, NR⁷C(O)NR⁷R⁷, NR⁷C(O)NR⁷R⁸, NR⁷(COOR⁷),NR⁷(COOR⁸), S(O)₂R⁷, S(O)₂R⁸, S(O)₂NR⁷R⁷, S(O)₂NR⁷R⁸, NR⁷S(O)₂NR⁷R⁸,NR⁷S(O)₂R⁷ or NR⁷S(O)₂R⁸, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I includes compoundswherein R⁵ is C(O)NR⁷R⁷, C(O)NR⁷R⁸, NR⁷C(O)R⁷, NR⁷C(O)R⁸, NR⁷C(O)NR⁷R⁷,NR⁷C(O)NR⁷R⁸, S(O)₂NR⁷R⁷, S(O)₂NR⁷R⁸, NR⁷S(O)₂NR⁷R⁸, NR⁷S(O)₂R⁷ orNR⁷S(O)₂R⁸, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I includes compoundswherein R⁵ is NR⁷R⁷, NR⁷R⁸, C(O)R⁷, C(O)R⁸, C(O)NR⁷R⁷, C(O)NR⁷R⁸,NR⁷C(O)R⁷, NR⁷C(O)R⁸, S(O)₂R⁷, S(O)₂R⁸, S(O)₂NR⁷R⁷, S(O)₂NR⁷R⁸,NR⁷S(O)₂R⁷ or NR⁷S(O)₂R⁸, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I includes compoundswherein R⁵ is —C(O)NR⁷R⁷, C(O)NR⁷R⁸, NR⁷C(O)R⁷, NR⁷C(O)R⁸, S(O)₂NR⁷R⁷,S(O)₂NR⁷R⁸, NR⁷S(O)₂R⁷ or NR⁷S(O)₂R⁸, in conjunction with any of theabove or below embodiments.

In another embodiment, the compounds of Formula I includes compoundswherein R⁵ is C(O)NR⁷R⁷, C(O)NR⁷R⁸, NR⁷C(O)R⁷ or NR⁷C(O)R⁸, inconjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I includes compoundswherein R⁵ is —C(O)NHC₁₋₆-alkyl, C(O)NHC₂₋₆-alkenyl, C(O)NHC₂₋₆-alkynyl,C(O)NHC₃₋₆-cycloalkyl, C(O)NHaryl, C(O)NHheteroaryl, NHC(O)C₁₋₆-alkyl,NHC(O)C₂₋₆-alkenyl, NHC(O)C₂₋₆-alkynyl, NHC(O)C₃₋₆-cycloalkyl,NHC(O)aryl or NHC(O)heteroaryl, in conjunction with any of the above orbelow embodiments.

In another embodiment, the compounds of Formula I includes compoundswherein R⁵ is C(O)NR⁷R⁷ or C(O)NR⁷R⁸, in conjunction with any of theabove or below embodiments.

In another embodiment, the compounds of Formula I includes compoundswherein R⁸ is a ring selected from phenyl, naphthyl, pyridyl, pyrimidyl,triazinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl,quinazolinyl, isoquinazolinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl,imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl,indolyl, isoindolyl, benzofuranyl, benzothiophenyl, benzimidazolyl,benzoxazolyl, benzisoxazolyl, benzopyrazolyl, benzothiazolyl,tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl,wherein said ring is optionally substituted independently with 1-3substituents of R⁹, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I includes compoundswherein R¹ is phenyl, naphthyl, pyridyl, pyrimidyl, triazinyl,pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, quinazolinyl,isoquinazolinyl, thiophenyl, furyl, tetrahydrofuryl, pyrrblyl,tetrahydropyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl,thiazolyl, oxazolyl, oxazolinyl, isoxazolyl, isoxazolinyl, oxadiazolyl,isothiazolyl, indolyl, indolinyl, isoindolyl, benzofuranyl,dihydrobenzofuranyl, benzothiophenyl, benzisoxazolyl, benzopyrazolyl,benzothiazolyl, benzimidazolyl, piperidinyl, pyranyl, cyclopropyl,cyclobutyl or cyclohexyl, each of which is optionally substitutedindependently with 1-3 substituents of R⁹;

each of R² and R³, independently, is H, halo, haloalkyl or C₁₋₁₀-alkyl;

R⁴ is CN, C(O)R⁷, C₁₋₄-alkylC(O)R⁷, methyl, ethyl, propyl, isopropyl,cyclopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl orC₁₋₄-alkyl-amino-C₁₋₄-alkyl or C₁₋₁₀-dialkylaminoC₁₋₄-alkyl-;

R⁵ is NR⁷R⁷, NR⁷R⁸, C(O)NR⁷R⁷, C(O)NR⁷R⁸, NR⁷C(O)R⁷, NR⁷C(O)R⁸,NR⁷C(O)NR⁷R⁷, NR⁷C(O)NR⁷R⁸, NR⁷(COOR⁷), NR⁷(COOR⁸), S(O)₂R⁷, S(O)₂R⁸,S(O)₂NR⁷R⁷, S(O)₂NR⁷R⁸, NR⁷S(O)₂NR⁷R⁸, NR⁷S(O)₂R⁷ or NR⁷S(O)₂R⁸;

each R⁶, independently, is H, F, Cl, Br, CF₃, —OCF₃, C₂F₅, —OC₂F₅,—O—C₁₋₄-alkyl, —C₁₋₄-alkyl-O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl,—C₁₋₄-alkyl-S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl, —N(C₁₋₆-alkyl)₂,—C₁₋₄-alkyl-NH—C₁₋₄-alkyl, —C₁₋₃-alkyl-N(C₁₋₄-alkyl)₂, NO₂, NH₂, CN,C₁₋₁₀-alkyl, the C₁₋₁₀-alkyl optionally substituted with one or moresubstituents of R⁹;

each R⁷, independently, is H, C₁₋₁₀-alkyl or C₃₋₁₀-cycloalkyl, whereinthe C₁₋₁₀-alkyl and C₃₋₁₀-cycloalkyl optionally comprising 1-4heteroatoms selected from N, O and S and optionally substituted with 1-3substituents of R⁹;

R⁸ is a ring selected from phenyl, naphthyl, pyridyl, pyrimidyl,triazinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl,quinazolinyl, isoquinazolinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl,imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl,indolyl, isoindolyl, benzofuranyl, benzothiophenyl, benzimidazolyl,benzoxazolyl, benzisoxazolyl, benzopyrazolyl, benzothiazolyl,tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl,wherein said ring is optionally substituted independently with 1-3substituents of R⁹; and

R⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, oxo, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxylor a saturated or partially or fully unsaturated 5-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S,wherein each of the C₁₋₁₀-allyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and each ring ofsaid ring system is optionally substituted independently with 1-3substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl.

In another embodiment, the compounds of Formula I includes compoundswherein R¹ is phenyl, naphthyl, pyridyl, pyrimidyl, triazinyl,pyridazinyl, pyrazinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl,imidazolyl, triazolyl, thiazolyl, oxazolyl, oxazolinyl, isoxazolyl,isoxazolinyl, oxadiazolyl, isothiazolyl, piperidinyl, pyranyl,cyclopropyl, cyclobutyl or cyclohexyl, each of which is optionallysubstituted independently with 1-3 substituents of R⁹;

each of R² and R³, independently, is H, F, Cl, CF₃, methyl or ethyl;

R⁴ is CN, C(O)R⁷, C₁₋₄-alkylC(O)R⁷, methyl, ethyl, propyl, isopropyl,cyclopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl orC₁₋₄-alkyl-amino-C₁₋₄-alkyl or C₁₋₁₀-dialkylaminoC₁₋₄-alkyl-;

R⁵ is C(O)NR⁷R⁷, C(O)NR⁷R⁸, NR⁷C(O)R⁷, NR⁷C(O)R⁸, NR⁷C(O)NR⁷R⁷,NR⁷C(O)NR⁷R⁸, S(O)₂NR⁷R⁷, S(O)₂NR⁷R⁸, NR⁷S(O)₂NR⁷R⁸, NR⁷S(O)₂R⁷ orNR⁷S(O)₂R⁸;

each R⁶, independently, is H, F, Cl, Br, CF₃, —OCF₃, C₂F₅,—O—C₁₋₃-alkyl, —S—C₁₋₃-alkyl, —NH—C₁₋₃-alkyl, NO₂, NH₂, OH, CN, methyl,ethyl propyl or isopropyl;

each R⁷, independently, is H, C₁₋₁₀-allyl or C₃₋₄-cycloalkyl, whereinthe C₁₋₆-alkyl and C₃₋₆-cycloalkyl optionally comprising 1-4 heteroatomsselected from N, O and S and optionally substituted with 1-3substituents of R⁹;

R⁸ is a ring selected from phenyl, pyridyl, pyrimidyl, triazinyl,pyridazinyl, pyrazinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl,imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl,tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl,wherein said ring is optionally substituted independently with 1-3substituents of R⁹; and

R⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, oxo, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxylor a saturated or partially or fully unsaturated 5-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S,wherein each of the Cl₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,Cl₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and each ring ofsaid ring system is optionally substituted independently with 1-3substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl.

In another embodiment, the compounds of Formula I includes compoundswherein R¹ is phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl,thiophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl,thiazolyl, oxazolyl, oxazolinyl, isoxazolyl, isoxazolinyl, oxadiazolylor isothiazolyl, each of which is optionally substituted independentlywith 1-3 substituents of R⁹;

each of R² and R³, independently, is H, F, Cl, CF₃ or methyl;

R⁴ is C₁₋₄-alkylC(O)R⁷, methyl, ethyl, propyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, pentyl, neopentyl orC₁₋₄-alkyl-amino-C₁₋₄-alkyl or C₁₋₄-dialkylaminoC₁₋₄-alkyl-;

R⁵ is C(O)NR⁷R⁷, C(O)NR⁷R⁸, NR⁷C(O)R⁷, NR⁷C(O)R⁸, NR⁷C(O)NR⁷R⁷,NR⁷C(O)NR⁷R⁸, S(O)₂NR⁷R⁷, S(O)₂NR⁷R⁸, NR⁷S(O)₂NR⁷R⁸, NR⁷S(O)₂R⁷ orNR⁷S(O)₂R⁸;

each R⁶, independently, is H, F, Cl, Br, CF₃, —OCF₃, C₂F₅,—O—C₁₋₃-alkyl, —S—C₁₋₃-alkyl, —NH—C₁₋₃-alkyl, NO₂, NH₂, OH, CN, methyl,ethyl propyl or isopropyl;

each R⁷, independently, is H, methyl, ethyl, propyl, isopropyl,cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of thecyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl optionallysubstituted with 1-3 substituents of R⁹;

R⁸ is a ring selected from phenyl, pyridyl, pyrimidyl, triazinyl,pyridazinyl, pyrazinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl,imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl,tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl,wherein said ring is optionally substituted independently with 1-3substituents of R⁹; and

R⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, oxo, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxylor a saturated or partially or fully unsaturated 5-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S,wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and each ring ofsaid ring system is optionally substituted independently with 1-3substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl.

In another embodiment, the compounds of Formula I includes compounds,and pharmaceutically acceptable salts thereof, selected fromN-cyclopropyl-3-(7-ethyl-1-(2-fluorophenyl)-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-5-fluoro-4-methylbenzamide;

-   N-cyclopropyl-3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-5-fluoro-4-methylbenzamide;-   N-cyclopropyl-3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylbenzamide;-   3-(1-(2-chlorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-cyclopropyl-5-fluoro-4-methylbenzamide;-   N-cyclopropyl-3-fluoro-5-(1-(2-fluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylbenzamide;-   3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methyl-N-(1-methyl-1H-pyrazol-5-yl)benzamide;-   N-cyclopropyl-3-(1-(2,4-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-5-fluoro-4-methylbenzamide;-   3-(1-(2-chlorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-cyclopropyl-4-methylbenzamide;-   N-cyclopropyl-3-(1-(2,4-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylbenzamide;-   N-cyclopropyl-4-methyl-3-(7-methyl-1-(2-methylphenyl)-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)benzamide;-   N-cyclopropyl-3-fluoro-4-methyl-5-(7-methyl-1-(2-methylphenyl)-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)benzamide;-   N-(3-(1-(2,4-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylphenyl)cyclopropanecarboxamide;-   N-cyclopropyl-3-fluoro-4-methyl-5-(7-methyl-1-(1-methylethyl)-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)benzamide;-   3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-3-isoxazolyl-4-methylbenzamide;-   3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-5-fluoro-N-3-isoxazolyl-4-methylbenzamide;-   N-cyclopropyl-4-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-5-methyl-2-pyridinecarboxamide;-   4-chloro-N-cyclopropyl-3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)benzamide;-   3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-5-fluoro-4-methyl-N-(1-methylethyl)benzamide;-   3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-5-fluoro-N,4-dimethylbenzamide;-   N-cyclopropyl-3-(1-(2,5-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-5-fluoro-4-methylbenzamide;-   N-cyclopropyl-3-(1-(2,5-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylbenzamide;-   3-(1-(2,5-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methyl-N-(1-methylcyclopropyl)benzamide;-   3-(1-(2,5-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-3-isoxazolyl-4-methylbenzamide;-   3-(1-(2,4-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-3-isoxazolyl-4-methylbenzamide;-   3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methyl-N-1,3-thiazol-2-ylbenzamide;-   4-chloro-N-cyclopropyl-3-(1-(2,5-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)benzamide;-   3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methyl-N-(1-methylcyclopropyl)benzamide;-   3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-5-fluoro-4-methylbenzamide;-   3-(1-(2,6-difluorobenzyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylbenzamide;-   3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methyl-N-(2-(methyloxy)-5-(trifluoromethyl)phenyl)benzamide;-   N-cyclopropyl-3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-(hydroxymethyl)benzamide;-   N-cyclopropyl-3-(1-(2,4-difluorophenyl)-7-ethyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylbenzamide;-   N-cyclopropyl-3-(1-(2,6-difluorophenyl)-7-methyl-6-thioxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylbenzamide;-   N-cyclopropyl-3-(1-(2,4-difluorophenyl)-7-(2,3-dihydroxypropyl)-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylbenzamide;-   N-cyclopropyl-3-(1-(4-fluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylbenzamide;-   4-chloro-N-cyclopropyl-3-(1-(4-fluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)benzamide;    and-   1-cyclopropyl-3-(3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylphenyl)urea.

In another embodiment, the compounds of Formula I include compounds, andpharmaceutically acceptable salts thereof, selected fromN-cyclopropyl-3-(7-ethyl-1-(2-fluorophenyl)-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-5-fluoro-4-methylbenzamide;

-   N-cyclopropyl-3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-5-fluoro-4-methylbenzamide;-   N-cyclopropyl-3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylbenzamide;-   3-(1-(2-chlorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-cyclopropyl-5-fluoro-4-methylbenzamide;-   N-cyclopropyl-3-fluoro-5-(1-(2-fluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylbenzamide;-   3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methyl-N-(1-methyl-1H-pyrazol-5-yl)benzamide;-   N-cyclopropyl-3-(1-(2,4-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-5-fluoro-4-methylbenzamide;-   3-(1-(2-chlorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-cyclopropyl-4-methylbenzamide;-   N-cyclopropyl-3-(1-(2,4-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylbenzamide;-   N-cyclopropyl-4-methyl-3-(7-methyl-1-(2-methylphenyl)-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)benzamide;-   N-cyclopropyl-3-fluoro-4-methyl-5-(7-methyl-1-(2-methylphenyl)-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)benzamide;-   N-(3-(1-(2,4-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylphenyl)cyclopropanecarboxamide;-   N-cyclopropyl-3-fluoro-4-methyl-5-(7-methyl-1-(1-methylethyl)-6-oxo-6,7-dihydro    1H-pyrazolo[3,4-b]pyridin-5-yl)benzamide;-   N-cyclopropyl-3-(1-(2,5-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-5-fluoro-4-methylbenzamide;-   N-cyclopropyl-3-(1-(2,5-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylbenzamide;-   3-(1-(2,5-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methyl-N-(1-methylcyclopropyl)benzamide;-   3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methyl-N-(1-methylcyclopropyl)benzamide;-   N-cyclopropyl-3-(1-(2,4-difluorophenyl)-7-ethyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylbenzamide;-   N-cyclopropyl-3-(1-(2,6-difluorophenyl)-7-methyl-6-thioxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylbenzamide;-   N-cyclopropyl-3-(1-(2,4-difluorophenyl)-7-(2,3-dihydroxypropyl)-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylbenzamide;-   N-cyclopropyl-3-(1-(4-fluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylbenzamide;-   4-chloro-N-cyclopropyl-3-(1-(4-fluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)benzamide;    and-   1-cyclopropyl-3-(3-(1,2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylphenyl)urea.

In another embodiment, the compounds of Formula I include compounds, andpharmaceutically acceptable salts thereof, selected fromN-cyclopropyl-3-(7-ethyl-1-(2-fluorophenyl)-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]-pyridin-5-yl)-5-fluoro-4-methylbenzamide;

-   N-cyclopropyl-3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-5-fluoro-4-methylbenzamide;-   N-cyclopropyl-3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylbenzamide;-   3-(1-(2-chlorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-cyclopropyl-5-fluoro-4-methylbenzamide;-   N-cyclopropyl-3-(1-(2,4-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-5-fluoro-4-methylbenzamide;-   3-(1-(2-chlorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-cyclopropyl-4-methylbenzamide;-   N-cyclopropyl-3-(1-(2,4-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylbenzamide;-   N-cyclopropyl-4-methyl-3-(7-methyl-1-(2-methylphenyl)-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)benzamide;-   N-cyclopropyl-3-fluoro-4-methyl-5-(7-methyl-1-(2-methylphenyl)-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)benzamide;-   N-(3-(1-(2,4-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylphenyl)cyclopropanecarboxamide;-   N-cyclopropyl-3-(1-(2,5-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-5-fluoro-4-methylbenzamide;-   N-cyclopropyl-3-(1-(2,5-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylbenzamide;-   N-cyclopropyl-3-(1-(2,4-difluorophenyl)-7-ethyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylbenzamide;-   N-cyclopropyl-3-(1-(4-fluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylbenzamide;-   4-chloro-N-cyclopropyl-3-(1-2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)benzamide;    and-   4-chloro-N-cyclopropyl-3-(1-(4-fluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)benzamide.

In another embodiment, the invention provides the compoundN-cyclopropyl-3-(1-(2,4-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-5-fluoro-4-methylbenzamide,or a pharmaceutically acceptable salt form thereof.

In another embodiment, the invention provides the compoundN-cyclopropyl-3-(1-(2,4-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylbenzamide,or a pharmaceutically acceptable salt form thereof.

In another embodiment, the invention provides the compoundN-(3-(1-(2,4-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylphenyl)cyclopropanecarboxamide,or a pharmaceutically acceptable salt form thereof.

In another embodiment, the invention provides the compoundN-cyclopropyl-3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylbenzamide,or a pharmaceutically acceptable salt form thereof.

In another embodiment, the invention provides the compound4-chloro-N-cyclopropyl-3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)benzamide,or a pharmaceutically acceptable salt form thereof.

In another embodiment, the invention provides the compound3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methyl-N-(1-methyl-1H-pyrazol-5-yl)benzamide,or a pharmaceutically acceptable salt form thereof.

In another embodiment, the compounds of Formula I includes compounds,and pharmaceutically acceptable salts thereof, selected from3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-3-isoxazolyl-4-methylbenzamide;

-   3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-5-fluoro-N-3-isoxazolyl-4-methylbenzamide;-   N-cyclopropyl-4-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-5-methyl-2-pyridinecarboxamide;-   4-chloro-N-cyclopropyl-3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)benzamide;-   3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-5-fluoro-4-methyl-N-(1-methylethyl)benzamide;-   3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-5-fluoro-N,4-dimethylbenzamide;-   3-(1-(2,5-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-3-isoxazolyl-4-methylbenzamide;-   3-(1-(2,4-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-3-isoxazolyl-4-methylbenzamide;-   3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methyl-N-1,3-thiazol-2-ylbenzamide;-   4-chloro-N-cyclopropyl-3-(1-(2,5-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)benzamide;-   3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-5-fluoro-4-methylbenzamide;-   3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylbenzamide;-   3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methyl-N-(2-(methyloxy)-5-(trifluoromethyl)phenyl)benzamide;    and-   N-cyclopropyl-3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-(hydroxymethyl)benzamide.

In another embodiment, the invention provides compounds of Formula I-B,and pharmaceutically acceptable salts thereof, wherein

B is O, S or N—CN;

R¹ is H, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl or C₃₋₁₀-cycloalkyl,each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyland C₄₋₁₀-cycloalkenyl optionally comprising 1-4 heteroatoms selectedfrom N, O and S and optionally substituted with one or more substituentsof R⁹,

or R¹ is a 3-8 membered monocyclic or 6-12 membered bicyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, saidheteroatoms selected from O, N, or S, wherein said ring system isoptionally substituted independently with one or more substituents ofR⁹;

each of R² and R³, independently, is H or halo;

R⁴ is CN, C(O)R⁷, C₁₋₄-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl orC₃₋₈-cycloalkyl, each of the C₁₋₆-alkyl, C₂₋₄-alkenyl, C₂₋₆-alkynyl andC₃₋₈-cycloalkyl optionally comprising 14 heteroatoms selected from N, Oand S and optionally substituted with one or more substituents of R⁹;

R⁵ is COOR⁷, COOR⁸, C(O)NR⁷R⁷, C(O)NR⁷R⁸, NR⁷C(O)R¹, NR⁷C(O)R⁸,NR⁷C(O)NR⁷R⁷, NR⁷C(O)NR⁷R⁸, S(O)₂NR⁷R⁷, S(O)₂NR⁷R⁸, NR⁷S(O)₂NR⁷R⁸,NR⁷S(O)₂R⁷ or NR⁷S(O)₂R⁸;

R^(6a) is H, halo, haloalkyl, NO₂, CN, OR⁷, NR⁷R⁷ or C₁₋₆-alkyl;

R^(6b) is H, halo, haloalkyl, NO₂, CN, OR⁷, NR⁷R⁷ or C₁₋₆-alkyl;

each R⁷, independently, is H, C₁₋₆-alkyl or C₃₋₆-cycloalkyl, each of theC₁₋₆-alkyl, and C₃₋₆-cycloalkyl optionally substituted with one or moresubstituents of R⁹;

R⁸ is a ring selected from phenyl, naphthyl, pyridyl, pyrimidyl,triazinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl,quinazolinyl, isoquinazolinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl,imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl,indolyl, isoindolyl, benzofuranyl, benzothiophenyl, benzimidazolyl,benzoxazolyl, benzisoxazolyl, benzopyrazolyl, benzothiazolyl,tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl,wherein said ring is optionally substituted independently with 1-3substituents of R⁹; and

R⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, oxo, C₁₋₁₀-alkyl,C210-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxylor a saturated or partially or fully unsaturated 5-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S,wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and each ring ofsaid ring system is optionally substituted independently with 1-3substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl.

In another embodiment, the invention provides compounds of Formula I-C,and pharmaceutically acceptable salts thereof, wherein

B is O, S or N—CN;

R¹ is H, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl or C₃₋₁₀-cycloalkyl,each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyland C₄₋₁₀-cycloalkenyl optionally comprising 14 heteroatoms selectedfrom N, O and S and optionally substituted with one or more substituentsof R⁹,

or R¹ is a 3-8 membered monocyclic or 6-12 membered bicyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, saidheteroatoms selected from O, N, or S, wherein said ring system isoptionally substituted independently with one or more substituents ofR⁹;

each of R² and R³, independently, is H or F;

R⁴ is CN, C(O)R⁷, C₁₋₄-alkyl, C₂₋₄-alkenyl, C₂₋₆-alkynyl orC₃₋₈-cycloalkyl, each of the C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl andC₃₋₈-cycloalkyl optionally comprising 14 heteroatoms selected from N, Oand S and optionally substituted with one or more substituents of R⁹;

R^(6a) is H, halo, haloalkyl, NO₂, CN, OR⁷, NR⁷R⁷ or C₁₋₆-alkyl;

R^(6b) is H, halo, haloalkyl, NO₂, CN, OR⁷, NR⁷R⁷ or C₁₋₆-alkyl;

each R⁷, independently, is H, C₁₋₄-alkyl or C₃₋₁₀-cycloalkyl, each ofthe C₁₋₆-alkyl, and C₃₋₆-cycloalkyl optionally substituted with one ormore substituents of R⁹;

R⁸ is a ring selected from phenyl, naphthyl, pyridyl, pyrimidyl,triazinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl,quinazolinyl, isoquinazolinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl,imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl,indolyl, isoindolyl, benzofuranyl, benzothiophenyl, benzimidazolyl,benzoxazolyl, benzisoxazolyl, benzopyrazolyl, benzothiazolyl,tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl,wherein said ring is optionally substituted independently with 1-3substituents of R⁹; and

R⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, oxo, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxylor a saturated or partially or fully unsaturated 5-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S,wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and each ring ofsaid ring system is optionally substituted independently with 1-3substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl.

In yet another embodiment, the compounds of Formulas I, I-B and I-Cinclude each individual example, and each and every pharmaceuticallyacceptable salt form thereof, described hereinbelow.

DEFINITIONS

The following definitions should assist in understanding the inventiondescribed herein.

The term “comprising” is meant to be open ended, including the indicatedcomponent(s), but not excluding other elements.

The term “C_(α-β)alkyl”, when used either alone or within other termssuch as “haloalkyl” and “alkylamino”, embraces linear or branchedradicals having α to β number of carbon atoms (such as C₁-C₁₀). Examplesof such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl and the like.The term “alkylenyl” embraces bridging divalent alkyl radicals such asmethylenyl and ethylenyl.

The term “alkenyl”, when used alone or in combination, embraces linearor branched radicals having at least one carbon-carbon double bond in amoiety having between two and ten carbon atoms. Examples of alkenylradicals include, without limitation, ethenyl, propenyl, alkyl,propenyl, butenyl and 4-methylbutenyl. The terms “alkenyl” and “loweralkenyl”, embrace radicals having “cis” and “trans” orientations, oralternatively, “E” and “Z” orientations, as appreciated by those ofordinary skill in the art.

The term “alkynyl”, when used alone or in combination, denotes linear orbranched radicals having at least one carbon-carbon triple bond andhaving two to ten carbon atoms. Examples of such radicals include,without limitation, ethynyl, propynyl (propargyl), butynyl, and thelike.

The term “alkoxy” or “alkoxyl”, when used alone or in combination,embraces linear or branched oxygen-containing radicals each having alkylportions of one or more carbon atoms. Examples of such radicals includemethoxy, ethoxy, propoxy, butoxy and tert-butoxy. Alkoxy radicals may befurther substituted with one or more halo atoms, such as fluoro, chloroor bromo, to provide “haloalkoxy” radicals. Examples of such radicalsinclude fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy,fluoroethoxy and fluoropropoxy.

The term “aryl”, when used alone or in combination, means a carbocyclicaromatic moiety containing one, two or even three rings wherein suchrings may be attached together in a fused manner. Every ring of an“aryl” ring system need not be aromatic, and the ring(s) fused to thearomatic ring may be partially or fully unsaturated and include one ormore heteroatoms selected from nitrogen, oxygen and sulfur. Thus, theterm “aryl” embraces aromatic radicals such as phenyl, naphthyl,indenyl, tetrahydronaphthyl, dihydrobenzafuranyl, anthracenyl, indanyl,benzodioxazinyl, and the like. Unless otherwise specified, the “aryl”group may be substituted, such as with 1 to 5 substituents includinglower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy and loweralkylamino, and the like. Phenyl substituted with —O—CH₂—O— or—O—CH₂—CH₂—O-forms an aryl benzodioxolyl substituent.

The term “carbocyclic”, also referred to herein as “cycloalkyl”, whenused alone or in combination, means a partially or fully saturated ringmoiety containing one (“monocyclic”), two (“bicyclic”) or even three(“tricyclic”) rings wherein such rings may be attached together in afused manner and formed from carbon atoms. Examples of saturatedcarbocyclic radicals include saturated 3 to 6-membered monocyclic groupssuch as cyclopropane, cyclobutane, cyclopentane and cyclohexane andpartially saturated monocyclic groups such as cyclopentene, cyclohexeneor cyclohexadiene. The partially saturated groups are also encompassedin the term “cycloalkenyl” as defined below.

The terms “ring” and “ring system” refer to a ring comprising thedelineated number of atoms, the atoms being carbon or, where indicated,a heteroatom such as nitrogen, oxygen or sulfur. Where the number ofatoms is not delineated, such as a “monocyclic ring system” or a“bicyclic ring system”, the numbers of atoms are 3-8 for a monocyclicand 6-12 for a bicyclic ring. The ring itself, as well as anysubstitutents thereon, may be attached at any atom that allows a stablecompound to be formed. The term “nonaromatic” ring or ring system refersto the fact that at least one, but not necessarily all, rings in abicyclic or tricyclic ring system is nonaromatic.

The terms “partially or fully saturated or unsaturated” and “saturatedor partially or fully unsaturated” with respect to each individual ring,refer to the ring either as fully aromatic (fully unsaturated),partially aromatic (or partially saturated) or fully saturated(containing no double or triple bonds therein). If not specified assuch, then it is contemplated that each ring (monocyclic) in a ringsystem (if bicyclic or tricyclic) may either be fully aromatic,partially aromatic or fully saturated, and optionally substituted withup to 5 substituents.

The term “cycloalkenyl”, when used alone or in combination, means apartially or fully saturated cycloalkyl containing one, two or eventhree rings in a structure having at least one carbon-carbon double bondin the structure. Examples of cycloalkenyl groups include C₃-C₆ rings,such as compounds including, without limitation, cyclopropene,cyclobutene, cyclopentene and cyclohexene. The term also includescarbocyclic groups having two or more carbon-carbon double bonds such as“cycloalkyldienyl” compounds. Examples of cycloalkyldienyl groupsinclude, without limitation, cyclopentadiene and cycloheptadiene.

The term “halo”, when used alone or in combination, means halogens suchas fluorine, chlorine, bromine or iodine atoms.

The term “haloalkyl”, when used alone or in combination, embracesradicals wherein any one or more of the alkyl carbon atoms issubstituted with halo as defined above. For example, this term includesmonohaloalkyl, dihaloalkyl and polyhaloalkyl radicals such as aperhaloalkyl. A monohaloalkyl radical, for example, may have either aniodo, bromo, chloro or fluoro atom within the radical. Dihalo andpolyhaloalkyl radicals may have two or more of the same halo atoms or acombination of different halo radicals. Examples of haloalkyl radicalsinclude fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl,difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,difluoropropyl, dichloroethyl and dichloropropyl. “Perfluoroalkyl”, asused herein, refers to alkyl radicals having all hydrogen atoms replacedwith fluoro atoms. Examples include trifluoromethyl andpentafluoroethyl.

The term “heteroaryl”, as used herein, either alone or in combination,means a fully unsaturated (aromatic) ring moiety formed from carbonatoms and having one or more heteroatoms selected from nitrogen, oxygenand sulfur. The ring moiety or ring system may contain one(“monocyclic”), two (“bicyclic”) or even three (“tricyclic”) ringswherein such rings are attached together in a fused manner. Every ringof a “heteroaryl” ring system need not be aromatic, and the ring(s)fused thereto (to the heteroaromatic ring) may be partially or fullysaturated and optionally include one or more heteroatoms selected fromnitrogen, oxygen and sulfur. The term “heteroaryl” does not includerings having ring members of —O—O—, —O—S— or —S—S—.

Examples of heteroaryl radicals, include unsaturated 5- to 6-memberedheteromonocyclyl groups containing 1 to 4 nitrogen atoms, including forexample, pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl,4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g.,4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl] andtetrazole; unsaturated 7- to 10-membered heterobicyclyl groupscontaining 1 to 4 nitrogen atoms, including for example, quinolinyl,isoquinolinyl, quinazolinyl, isoquinazolinyl, aza-quinazolinyl, and thelike; unsaturated 5- to 6-membered heteromonocyclic group containing anoxygen atom, for example, pyranyl, 2-furyl, 3-furyl, benzofuryl, etc.;unsaturated 5 to 6-membered heteromonocyclic group containing a sulfuratom, for example, 2-thienyl, 3-thienyl, benzothienyl, etc.; unsaturated5- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atomsand 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl,oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,5-oxadiazolyl]; unsaturated 5 to 6-membered heteromonocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example,thiazolyl, isothiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl].

The term “heteroaryl” also embraces bicyclic radicals wherein 5- or6-membered heteroaryl radicals are fused/condensed with aryl radicals orunsaturated condensed heterocyclic groups containing 1 to 5 nitrogenatoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl,quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl[e.g., tetrazolo[1,5-b]pyridazinyl]; unsaturated condensed heterocyclicgroup containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.benzoxazolyl, benzoxadiazolyl]; unsaturated condensed heterocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,benzothiazolyl, benzothiadiazolyl]; and saturated, partially unsaturatedand unsaturated condensed heterocyclic group containing 1 to 2 oxygen orsulfur atoms [e.g. benzofuryl, benzothienyl,2,3-dihydro-benzo[1,4]dioxinyl and dihydrobenzofuryl]. Examples ofheterocyclic radicals include five to ten membered fused or unfusedradicals.

The term “heterocyclic”, when used alone or in combination, means apartially or fully saturated ring moiety containing one, two or eventhree rings wherein such rings may be attached together in a fusedmanner, formed from carbon atoms and including one or more heteroatomsselected from N, O or S. Examples of heterocyclic radicals includesaturated 3 to 6-membered heteromonocyclic groups containing 1 to 4nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidinyl,pyrrolinyl, piperazinyl]; saturated 3 to 6-membered heteromonocyclicgroup containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.morpholinyl]; saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,thiazolidinyl]. Examples of partially saturated heterocyclyl radicalsinclude dihydrothienyl, dihydropyranyl, dihydrofuryl anddihydrothiazolyl.

Examples of partially saturated and saturated heterocyclyl include,without limitation, pyrrolidinyl, imidazolidinyl, piperidinyl,pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl,thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl,indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl,isochromanyl, chromanyl, 1,2-dihydroquinolyl,1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4-tetrahydro-quinolyl,2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl,5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl,3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl,2,3-dihydro-1H-1λ′-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuryland dihydrothiazolyl, and the like.

The term “alkylamino” includes “N-alkylamino” where amino radicals areindependently substituted with one alkyl radical. Preferred alkylaminoradicals are “lower alkylamino” radicals having one to six carbon atoms.Even more preferred are lower alkylamino radicals having one to threecarbon atoms. Examples of such lower alkylamino radicals includeN-methylamino, and N-ethylamino, N-propylamino, N-isopropylamino and thelike.

The term “dialkylamino” includes “N,N-dialkylamino” where amino radicalsare independently substituted with two alkyl radicals. Preferredalkylamino radicals are “lower alkylamino” radicals having one to sixcarbon atoms. Even more preferred are lower alkylamino radicals havingone to three carbon atoms. Examples of such lower alkylamino radicalsinclude N,N-dimethylamino, N,N-diethylamino, and the like.

The term “aminocarbonyl” denotes an amide group of the formula—C(═O)NH₂.

The terms “alkylthio” and “thioalkoxyl” embrace radicals containing alinear or branched alkyl radical, of one to ten carbon atoms, attachedto a divalent sulfur atom. An example of “alkylthio” is methylthio,(CH₃S—).

The term “Formula I” includes any sub formulas, such as Formulas I-B andI-C.

The term “pharmaceutically-acceptable” when used with reference to acompound of Formulas I, I-B and I-C is intended to refer to a form ofthe compound that is safe for administration. For example, a free base,a salt form, a solvate, a hydrate, a prodrug or derivative form of acompound of Formula I, I-B or of Formula I-C, which has been approvedfor mammalian use, via oral ingestion or any other route ofadministration, by a governing body or regulatory agency, such as theFood and Drug Administration (FDA) of the United States, ispharmaceutically acceptable.

Included in the compounds of Formulas I, I-B and I-C are thepharmaceutically acceptable salt forms of the free-base compounds. Theterm “pharmaceutically-acceptable salts” embraces salts, commonly usedto form alkali metal salts and to form addition salts of free acids orfree bases, which have been approved by a regulatory agency. Asappreciated by those of ordinary skill in the art, salts may be formedfrom ionic associations, charge-charge interactions, covalent bonding,complexation, coordination, etc. The nature of the salt is not critical,provided that it is pharmaceutically acceptable.

Suitable pharmaceutically acceptable acid addition salts of compounds ofFormulas I and I-B may be prepared from an inorganic acid or from anorganic acid. Examples of such inorganic acids are hydrochloric,hydrobromic, hydroiodic, hydrofluoric, nitric, carbonic, sulfonic,sulfuric and phosphoric acid. Appropriate organic acids may be selectedfrom aliphatic, cycloaliphatic, aromatic, arylaliphatic, heterocyclic,carboxylic and sulfonic classes of organic acids, examples of whichinclude, without limitation, formic, acetic, adipic, butyric, propionic,succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic,glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic,anthranilic, mesylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic(pamoic), methanesulfonic, ethanesulfonic, ethanedisulfonic,benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic,sulfanilic, cyclohexylaminosulfonic, camphoric, camphorsulfonic,digluconic, cyclopentanepropionic, dodecylsulfonic, glucoheptanoic,glycerophosphonic, heptanoic, hexanoic, 2-hydroxy-ethanesulfonic,nicotinic, 2-naphthalenesulfonic, oxalic, palmoic, pectinic,persulfuric, 2-phenylpropionic, picric, pivalic propionic, succinic,thiocyanic, undecanoic, stearic, algenic, β-hydroxybutyric, salicylic,galactaric and galacturonic acid. Suitable pharmaceutically-acceptablebase addition salts of compounds of Formulas I and II include metallicsalts, such as salts made from aluminum, calcium, lithium, magnesium,potassium, sodium and zinc, or salts made from organic bases including,without limitation, primary, secondary and tertiary amines, substitutedamines including cyclic amines, such as caffeine, arginine,diethylamine, N-ethyl piperidine, histidine, glucamine, isopropylamine,lysine, morpholine, N-ethyl morpholine, piperazine, piperidine,triethylamine, disopropylethylamine and trimethylamine. All of thesesalts may be prepared by conventional means from the correspondingcompound of the invention by reacting, for example, the appropriate acidor base with the compound of Formulas I and I-B.

Also, the basic nitrogen-containing groups can be quaternized with suchagents as lower alkyl halides, such as methyl, ethyl, propyl, and butylchloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl,dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl,myristyl and stearyl chlorides, bromides and iodides, aralkyl halideslike benzyl and phenethyl bromides, and others. Water or oil-soluble ordispersible products are thereby obtained.

Examples of acids that may be employed to form pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid (HCl), hydrobromic acid (HBr), citric acid, sulphuricacid and phosphoric acid and such organic acids as oxalic acid, stearicand, salicylic acid, pamoic acid, gluconic acid, ethanesulfonic acid,methanesulfonic acid (MSA), benzenesulfonic acid (BSA), toluenesulfonicacid, tartaric acid, fumaric acid, medronic acid, napsylic acid, maleicacid, succinic acid and citric acid. Other examples include salts withalkali metals or alkaline earth metals such as sodium, potassium,calcium or magnesium, or with organic bases.

Additional examples of such salts can be found in Berge et al., J.Pharm. Sci., 66, 1 (1977). Conventional methods may be used to form thesalts. For example, a phosphate salt of a compound of the invention maybe made by combining the desired compound free base in a desiredsolvent, or combination of solvents, with phosphoric acid in a desiredstoichiometric amount, at a desired temperature, typically under heat(depending upon the boiling point of the solvent). The salt can beprecipitated upon cooling (slow or fast) and may crystallize (i.e., ifcrystalline in nature), as appreciated by those of ordinary skill in theart. Further, hemi-, mono-, di, tri- and poly-salt forms of thecompounds of the present invention are also contemplated herein.Similarly, hemi-, mono-, di, tri- and poly-hydrated forms of thecompounds, salts and derivatives thereof, are also contemplated herein.

The term “derivative” is broadly construed herein, and intended toencompass any salt of a compound of this invention, any ester of acompound of this invention, or any other compound, which uponadministration to a patient is capable of providing (directly orindirectly) a compound of this invention, or a metabolite or residuethereof, characterized by the ability to the ability to modulate akinase enzyme.

The term “pharmaceutically-acceptable derivative” as used herein,denotes a derivative, which is pharmaceutically acceptable.

The term “prodrug”, as used herein, denotes a compound which uponadministration to a subject or patient is capable of providing (directlyor indirectly) a compound of this invention. Examples of prodrugs wouldinclude esterified or hydroxylated compounds where the ester or hydroxylgroups would cleave in vivo, such as in the gut, to produce a compoundaccording to Formulas I, I-B and I-C. A “pharmaceutically-acceptableprodrug” as used herein, denotes a prodrug, which is pharmaceuticallyacceptable. Pharmaceutically acceptable modifications to the compoundsof Formula I are readily appreciated by those of ordinary skill in theart.

The compound(s) of Formulas I, I-B and I-C may be used to treat asubject by administering the compound(s) as a pharmaceuticalcomposition. To this end, the compound(s) can be combined with one ormore carriers, diluents or adjuvants to form a suitable composition,which is described in more detail herein.

The term “excipient”, as used herein, denotes any pharmaceuticallyacceptable additive, carrier, adjuvant, or other suitable ingredient,other than the active pharmaceutical ingredient (API), which istypically included for formulation and/or administration purposes.“Diluent” and “adjuvant” are defined hereinafter.

The terms “treat”, “treating,” “treatment,” and “therapy” as used hereinrefer to therapy, including without limitation, curative therapy,prophylactic therapy, and preventative therapy. Prophylactic treatmentgenerally constitutes either preventing the onset of disordersaltogether or delaying the onset of a pre-clinically evident stage ofdisorders in individuals.

The phrase “effective dosage amount” is intended to quantify the amountof each agent, which will achieve the goal of improvement in disorderseverity and the frequency of incidence over treatment of each agent byitself, while avoiding adverse side effects typically associated withalternative therapies.

The term “leaving groups” (also denoted as “LG”) generally refer togroups that are displaceable by a nucleophile. Such leaving groups areknown in the art. Examples of leaving groups include, but are notlimited to, halides (e.g., I, Br, F, Cl), sulfonates (e.g., mesylate,tosylate), sulfides (e.g., SCH₃), N-hydroxsuccinimide,N-hydroxybenzotriazole, and the like. Nucleophiles are species that arecapable of attacking a molecule at the point of attachment of theleaving group causing displacement of the leaving group. Nucleophilesare known in the art. Examples of nucleophilic groups include, but arenot limited to, amines, thiols, alcohols, Grignard reagents, anionicspecies (e.g., alkoxides, amides, carbanions) and the like.

General Synthetic Procedures

The present invention further comprises procedures for the preparationof compounds of Formulas I, I-B and I-C. The compounds of Formulas I,I-B and I-C can be synthesized according to the procedures described inthe following Schemes 1-8 (corresponding to general Methods A, B, D, E,F, G, H and I, respectively) and scheme 9, wherein the substituents areas defined for Formulas I and I-B, above, except where further noted.The synthetic methods described below are merely exemplary, and thecompounds of the invention may also be synthesized by alternate routesas appreciated by persons of ordinary skill in the art.

The following list of abbreviations used throughout the specificationrepresent the following and should assist in understanding theinvention:

-   ACN, MeCN—acetonitrile-   BSA—bovine serum albumin-   BOP—benzotriazol-1-yl-oxy hexafluorophosphate-   Br₂—bromine-   CDI—carbonyldiimidazole-   CS₂CO₃— cesium carbonate-   CHCl₃—chloroform-   CH₂Cl₂, DCM—dichloromethane, methylene chloride-   DCC—dicyclohexylcarbodiimide-   DIC—1,3-diisopropylcarbodiimide-   DIEA,(iPr)₂Net—diisopropylethylamine-   DME—dimethoxyethane-   DMF—dimethylformamide-   DMAP—4-dimethylaminopyridine-   DMSO—dimethylsulfoxide-   EDC—1-(3-dimethylaminopropyl)-3-ethylcarbodiimide-   Et₂O—diethyl ether-   EtOAc—ethyl acetate-   G, g, gm—gram-   h,hr—hour-   H₂—hydrogen-   H₂O—water-   HATU—O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate-   HBr—hydrobromic acid-   HCl—hydrochloric acid-   HOBt—1-hydroxybenzotriazole hydrate-   HOAc—acetic acid-   HPLC—high pressure liquid chromatography-   IPA, IpOH—isopropyl alcohol-   K₂CO₃—potassium carbonate-   LG—leaving group-   MgSO₄—magnesium sulfate-   MS—mass spectrum-   MeOH—methanol-   N₂—nitrogen-   NaCNBH₃—sodium cyanoborohydride-   Na₂CO₃—sodium carbonate-   NaHCO₃—sodium bicarbonate-   NaH—sodium hydride-   NaOCH₃—sodium methoxide-   NaOH—sodium hydroxide-   Na₂SO₄—sodium sulfate-   NBS—N-bromosuccinimide-   NH₄Cl—ammonium chloride-   NH₄OH—ammonium hydroxide-   NMP—N-methylpyrrolidinone-   P(t-bu)₃—tri(tert-butyl)phosphine-   PBS—phosphate buffered saline-   Pd/C—palladium on carbon-   Pd(PPh₃)₄—palladium(0)triphenylphosphine tetrakis-   Pd(dppf)Cl₂-palladium(1,1-bisdiphenylphosphinoferrocene) II chloride-   Pd(OAc)₂—palladium acetate-   PyBop—benzotriazol-1-yl-oxy-tripyrrolidino-phosphonium    hexafluorophosphate-   RT, rt—room temperature-   TBTU—O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium    tetrafluoroborate-   TEA, Et₃N—triethylamine-   TFA—trifluoroacetic acid-   THF—tetrahydrofuran-   UV—ultraviolet light

Phenyl-substituted pyrazolo-pyridinones 8, (where each of A¹⁻⁴ inFormula I is CH or CR⁶ and R⁵ as shown is an amide linker; the ringshown as a phenyl ring in scheme 1 is generally referred to throughoutthe specification as the “B” ring) may be made by the method generallydescribed in Scheme 1, also designated herein as Method A. As shown, anamino pyrazolo-carbaldehyde 3 may be made from the reaction of anappropriate substituted hydrazine 1 (or its HCl salt) with2-(ethoxymethylene) malononitrile followed by the Raney-Nickel catalyzedhydrogenation of the 4-carbonitrile-pyrazole to the4-carbaldehyde-pyrazole 3. Pyrazole 3 can then be reacted with methylp,p-bis(2,2,2-trifluoroethyl)-phosphonoacetate in the presence of excessKHMDS, at suitable temperatures, to afford the cyclizedpyrazolo-pyridinone intermediate 4. Alkylation of pyridinone 4 generallyyields a mixture of non-selective region-isomeric alkylated products 5and 6, as shown. Upon purification and isolation of the desiredR⁴-substituted pyrazolo-pyridinone 5, it may be brominated to afford thecorresponding bromine adduct 7, which can be subjected to suitableSuzuki Coupling conditions, such as those shown in scheme 1, with adesired boronic ester intermediate 9 to afford the desired substitutedpyrazolo-pyridinone 8.

The boronic ester intermediates 9 may be prepared by methods describedin the following references: (1) PCT Int. Patent Appl. No. WO2005073189, titled “Preparation of fused heteroaryl derivatives as p38kinase inhibitors” or (2) PCT Int. Patent Appl. No. WO 2006094187,titled “Preparation of phthalazine, aza- and diaza-phthalazine compoundsas protein kinase, especially p38 kinase, inhibitors for treatinginflammation and related conditions”, both publications of which arehereby incorporated herein by reference in their entirety.

The Suzuki method is a reaction using a borane reagent, such as adioxaborolane intermediate 9 (also described in scheme 3 below as aborane B-A intermediate 8), and a suitable leaving group containingreagent, such as the Br-pyrazolo-pyridinone 7 (Br is a suitable halogenleaving group “LG”). As appreciated to one of ordinary skill in the art,Suzuki reactions also utilize a palladium catalyst. Suitable palladiumcatalysts include Pd(PPh₃)₄, Pd(OAc)₂ or Pd(dppf)Cl₂. Where LG is ahalide, the halide may be an iodide, a bromide or even a chloride(chloro-pyridyl or chloro-picolinyl B rings undergo Suzuki reactions inthe presence of Pd(OAc)₂). Other LGs are also suitable. For example,Suzuki couplings are known to occur with a sulfonate, such astrifluoromethanesulfonate, as the leaving group.

The Suzuki reaction conditions may vary. For example, Suzuki reactionsare generally run in the presence of a suitable base such as a carbonatebase, bicarbonate or an acetate base, in a suitable solvent such astoluene, acetonitrile, DMF or an aqueous-organic solvent combination ora biphasic system of solvents. Further, the reaction may require heatdepending upon the particular pyrazolo-pyridinone 7 and/or boronic acidor ester 9, as appreciated by those skilled in the art. In addition,where the B ring is an aromatic moiety, such as phenyl, the reaction maybe complete in a short period of time with heat.

Other methods of installing the boronate on a desired aromatic ring areknown. For example metal coupling chemistry, such Stille, Kumada,Negishi coupling methods, and the like, may be employed to thepyrazolo-pyridinone cores 5 or 7 to prepare desired cyclicB-ring-substituted intermediates.

Alternatively, substituted pyrazolo-pyridinones 8, (where each of A¹⁻⁴independently, is either N or CR⁶ and R⁵ as shown is an amide linker;the ring shown as a phenyl or pyridyl ring in scheme 2 is generallyreferred to throughout the specification as the “B” ring) may be made bythe method generally described in Scheme 1, also designated herein asMethod B. In method B, pyrazole 10 can be treated with diethyl malonatein the presence of piperidine to provide the bicyclicpyrazolo-pyridinone intermediate 11. Saponification of the ester groupto the corresponding acid moiety of intermediate 11, followed bybromination with a suitable bromine delivery agent, such as NBS, affordsthe corresponding bromine intermediate 12. Compound 12 can be subject toalkylation or other functionalization, such as methylation as shownabove, to provide the R⁴ substituted intermediate 13, as appreciated bythose of ordinary skill in the art. The corresponding bromine adduct 13,can be subjected to suitable Suzuki Coupling conditions, such as thoseshown in scheme 1, with a desired boronic ester intermediate 9 to affordthe desired substituted pyrazolo-pyridinone 8.

Alternatively, substituted pyrazolo-pyridinones 21, (where each of A¹⁻⁴independently, of the B ring is either N or CR⁶ and R⁵ as shown is anamide linker) may be made by the method generally described in Scheme 3,also designated herein as Method D. In method D, bromopyrazolo-pyridinone 18 can be reacted with a desired B-ring substitutedboronic acid 19 in the presence of a suitable palladium catalyst, suchas those shown or described in schemes 2 and 3 above, to provide thepyrazolo-pyridinone intermediate 11. Saponification of the ester groupto the corresponding acid moiety of intermediate 20 with the carboxylidacid available to vary the linker region R⁵ of Formulas I and II, aswell the desired R⁷, R⁸ and R⁹ groups which are attached therefrom. Forexample, and as shown in scheme 4, the acid of compounds 20 can beactivated to coupling via various well known acid LG's, such asconversion to the corresponding acid chloride species as shown, followedby treatment with a suitable primary or secondary nucleophilic moiety,such as an appropriately substituted amine as shown, to afford hecorresponding desired pyrazolo-pyridinone product 21.

Alternatively, substituted pyrazolo-pyridinones 21, (where each of A¹⁴independently, of the B ring is either N or CR⁶ and R⁵ as shown is anamide linker) may be made by the method generally described in Scheme 4,also designated herein as Method E. In method E, t-butyl protectedpyrazolo-pyridinone 22 can be brominated by reaction with a suitablebromine source in the presence of a suitable acid, such as glacialacetic acid as shown. The bromide adduct 23 can then be alkylated(shown) or acylated (not shown), or a desired R¹ group can be inserted,on the available pyrazole nitrogen under basic conditions, such as thosedescribed in scheme 1 or those shown above. The corresponding R¹ groupfunctionalized adduct 24 can be subjected to suitable Suzuki couplingconditions, such as those shown in scheme 1, with a desired boronicester intermediate 9 (not shown in scheme 4) to afford the desiredsubstituted pyrazolo-pyridinone 21.

Substituted pyrazolo-pyridinones 29 (where each of A¹⁻⁴ independently,of the B ring is CR⁶ and R⁵ as shown is an amide linker) may be made bythe method generally described in Scheme 5, also designated herein asMethod F. In method F, the methyl group of bromo-benzoate 25 can beacetylated by first reaction with a suitable bromine source, such asNBS, in the presence of an acetate salt and a suitable acid, such aspotassium acetate and acetic acid as shown. The bromide of the acetateadduct 26 can then be converted to the corresponding boronate 27 (asshown; see schemes 1 and 3), and the methyl benzoate intermediate 27 canbe reacted with pyrazolo-pyridinone 24 under suitable Suzuki orSuzuki-like coupling conditions, such as those shown above and in scheme1, to afford the coupled intermediate (not shown) which ester ishydrolized during basic work-up to afford acid 28. Acid 28 can beconverted to the corresponding amide under conventional conditions usingknown reagents, such as those shown above and those described in scheme3 above and scheme 9 below.

Substituted pyrazolo-pyridinones 35 (where each of A¹⁻⁴, independently,of the B ring is CR⁶ and R⁵ as shown is CN) may be made by the methodgenerally described in Scheme 6, also designated herein as Method G. Inmethod G, the nitro group of chloro-bromo-nitrobenzene 30 can be reducedusing conventional methods, such as by hydrogenation, to afford the freeamine 31. Amine 31 can be first protected with a suitable protectinggroup such as BOC, and then converted to the corresponding boronate 32(as shown; see scheme 1). Boronate intermediate 32 can be reacted withpyrazolo-pyridinone 24 under suitable Suzuki or like couplingconditions, such as those shown above and in scheme 1, to afford thecoupled intermediate 33. Boc amine 33 can be converted to thecorresponding iodide 34 under conventional conditions, such as by firstremoving the BOc group and converting the resulting amine to iodideusing known reagents, such as those shown above. Iodide 34 can beconverted to the corresponding cyano group under conventionalconditions, such as those described above.

Substituted pyrazolo-pyridinethiones 29A may be made by the methodgenerally described in Scheme 7, also designated herein as Method H, Inmethod H, the ketone of the bromo-pyrazolo-pyridinone intermediate 24can be converted to the corresponding thio-ketone 24A using conventionalmethods, such as with Lawessen's Reagent under suitable conditions.Thio-ketone 24A can be reacted with a boronate 9A (as shown in Method A,scheme 1) under suitable Suzuki or Suzuki-like coupling conditions toafford the coupled adduct 29A.

Substituted pyrazolo-pyridinones 38 may be made by the method generallydescribed in Scheme 8, also designated herein as Method I. In method I,the amide nitrogen of the bromo-pyrazolo-pyridinone intermediate 12A canbe functionalized or substituted using a method described in scheme 2,to install an allyl group (as shown) for example, and affordintermediate 13A. The allyl group of 13A may further be functionalized,such as oxidized (as shown) to the corresponding dihydroxideintermediate 37 using conventional oxidizing agents, such as osmium asshown. Intermediate 37 can be reacted with a boronate 9A (as shown inMethod A, scheme 1) under suitable Suzuki or Suzuki-like couplingconditions to afford the coupled adduct 38. This method provides aneffective process for varying the R⁴ group in compounds of Formulas I,I-B and I-C.

Various other linker R⁵ groups are within the scope of the presentinvention. Such other linkers may be made using the general methodsdescribed in scheme 9 below. As illustrate in scheme 9, desirable R¹ andR⁸ groups are shown as a ring designated as ring A. However, the presentinvention is not so limited, and it is intended that what is depicted as“ring A” in scheme 9 should be read to also include non cyclic moietiesattached to linker R⁵, as described in Formulas I, I-B and I-C herein.

The B ring, as illustrated in scheme 9, is substituted by a linker groupR⁵. The R⁵ linker group, including an amino, a carboxyl, a sulfonyl, anamido or a urea linker, as defined herein in Formulas I, I-B and I-C,connect various substitutions, including R⁷ non-cyclic moieties or R⁷and R⁸ cyclic rings (generally designated and referred to in Scheme 10,and throughout the specification, as the “A” group or “A” ring) to the“B” ring. This linker may be attached by various coupling methods asdescribed in Scheme 9. Each of the nine sub-schemes, numbered 1-9 aboveand described below, utilize the following meanings for (R)_(n), X, Nu⁻,E⁺ and m: (R)_(n) refers to n number of R⁶, R⁷ and R⁸ substitutionswherein n is an integer from 0-5; X refers generally to a “leavinggroup” (also referred to herein as “LG”) such as a halide (bromine,chlorine, iodine or fluorine), alkylsulfonate and other known groups(also see definitions herein); Nu⁻ refers generally to a nucleophilicspecies such as a primary or secondary amine, an oxygen, a sulfur or aanionic carbon species—examples of nucleophiles include, withoutlimitation, amines, hydroxides, alkoxides and the like; E+refersgenerally to an electrophilic species, such as the carbon atom of acarbonyl, which is susceptible to nucleophilic attack or readilyeliminates—examples of suitable electrophilic carbonyl species include,without limitation, acid halides, mixed anhydrides, aldehydes,carbamoyl-chlorides, sulfonyl chlorides, acids activated with activatingreagents such as TBTU, HBTU, HATU, HOBT, BOP, PyBOP and carbodiimides(DCC, EDC, CDI and the like), and other electrophilic species includinghalides, isocyanates, daizonium ions and the like; and m is either 0 or1.

The coupling of ring B to A, as shown as products in sub-schemes 1-9,can be brought about using various conventional methods to link ring Band A together. For example, an amide or a sulfonamide linkage, as shownin sub-schemes 2 and 4, and 7 and 9 where the Nu− is an amine,respectively, can be made utilizing an amine on either the B or A groupsand an acid chloride or sulfonyl chloride on the other of either the Bor A groups. The reaction proceeds generally in the presence of asuitable solvent and/or base. Suitable solvents include, withoutlimitation, generally non-nucleophilic, anhydrous solvents such astoluene, CH₂Cl₂, THF, DMF, DMSO, N,N-dimethylacetamide and the like,including solvent combinations thereof. The solvent may range inpolarity, as appreciated by those skilled in the art. Suitable basesinclude, for example, tertiary amine bases such as DIEA, TEA, carbonatebases such as Na₂CO₃, K₂CO₃, Cs₂CO₃, hydrides such as NaH, KH,borohydrides, cyanoborohydrides and the like, alkoxides such as NaOCH₃,and the like. The base itself may also serve as a solvent. The reactionmay optionally be run neat, i.e., without any base and/or solvent. Thesecoupling reactions are generally fast and conversion occurs typically inambient conditions. However, depending upon the particular substrate,such reactions may require heat, as appreciated by those skilled in theart.

Similarly, carbamates as illustrated in sub-schemes 5 and I where Nu− isan amine, anhydrides as illustrated in sub-scheme 1 where Nu− is anoxygen, reverse amides as generally illustrated in sub-scheme 8 whereNu− is an amine and E+ is an acid chloride, ureas as illustrated insub-scheme 3, thioamides and thioureas where the respective carbonyloxygen is a sulfur, thiocarbamates where the respective carbonyl oxygenand/or carbamate oxygen is a sulfur, and the like. While the abovemethods are so described, they are not exhaustive, and other methods forlinking groups A and B together may be utilized as appreciated by thoseskilled in the art.

Although sub-schemes 1-9 are illustrated as having the nucleophilic andelectrophilic coupling groups, such as the amino group and acid chloridegroups illustrated in sub-scheme 2, directly attached to the substrate,either the A group or B ring, in question, the invention is not solimited. It is contemplated herein that these nucleophilic and/orelectrophilic coupling groups may be tethered from their respectivering. For example, the amine group on the B ring, and/or the acid halidegroup on the A group or ring, as illustrated in sub-scheme 2, may beremoved from direct attachment to the ring by a one or more atom spacer,such as by a methylene, ethylene spacer or the like. As appreciated bythose skilled in the art, such spacer may or may not affect the couplingreactions described above, and accordingly, such reaction conditions mayneed to be modified to effect the desired transformation.

The coupling methods described in sub-schemes 1-9 of scheme 6 are alsoapplicable for coupling desired A groups or rings to desiredpyrazolo-pyridinone-B ring intermediates, such as to substituted B ringcarboxylic acids (Example 2) to synthesize desired compounds of FormulasI, I-B and I-C. For example, a desirably substitutedpyrazolo-pyridinone-benzoic acid maybe reacted with a desirablysubstituted primary or secondary, amine, such as an NHR⁷R⁷ or NHR⁷R⁸group in the presence of a suitable solvent and a known couplingreagent, such as TBTU, HATU, CDI or others, to prepare the desired A-Bamide bond, and the final compound of Formulas I or I-B.

Note that the B-A moiety is connected through a linker “L”. “L” may beany linker generally defined by the R⁵ groups in Formulas I, I-B andI-C, and particularly, it includes, without limitation, an amide, aurea, a thiourea, a thioamide, a carbamate, an anhydride, a sulfonamideand the like, allowing for spacer atoms either between ring B and Land/or between ring or group A and L, as described in Scheme 6 above.

To enhance the understanding and appreciation of the present invention,the following specific examples (starting reagents, intermediates andcompounds of Formulas I, I-B and I-C) and methods of making compounds ofthe invention are set forth. It should be appreciated that the abovegeneral methods and specific examples below are merely for illustrativepurposes only and are not to be construed as limiting the scope of thisinvention in any manner. The following analytical methods were used topurify and/or characterize the compounds, and intermediates, describedin the examples below.

Analytical Methods:

Unless otherwise indicated, all HPLC analyses were run on a AgilentModel 1100 system with an Agilent Technologies Zorbax SB-C₈(5μ) reversephase column (4.6×150 mm; Part no. 883975-906) run at 30° C. with a flowrate of about 1.50 mL/min. The mobile phase used solvent A (H₂O/0.1%TFA) and solvent B (ACN/0.1% TFA) with a 11 min gradient from 5% to 100%ACN. The gradient was followed by a 2 min. return to 5% ACN and about a2.5 min. re-equilibration (flush).

LC-MS Method:

Samples were run on an Agilent model-1100 LC-MSD system with anPhenomenex Synergi MAX-RP (4.0μ) reverse phase column (2×50 mm) at 40°C. The flow rate was constraint and ranged from about 0.75 mL/min toabout 1.0 mL/min.

The mobile phase used a mixture of solvent A (H₂O/0.1% TFA) and solventB (ACN/0.1% TFA) with a5 min time period for a gradient from 10% to 100%solvent B. The gradient was followed by a 0.5 min period to return to10% solvent B and a 1.5 min 10% solvent B re-equilibration (flush) ofthe column.

Preparative HPLC Method:

Where indicated, compounds of interest were purified via reverse phaseHPLC using a Gilson workstation utilizing one of the following twocolumns and methods: (A) Using a 50×100 mm column (Waters, Exterra, C18,5 microns) at 50 mL/min. The mobile phase used was a mixture of solventA (H₂O/10 mM ammonium carbonate at pH about 10, adjusted with conc.NH₄OH) and solvent B (85:15 ACN/water, 10 mM ammonium carbonate at pH ofabout 10 adjusted with conc. NH₄OH). Each purification run utilized a 10minute gradient from 40% to 100% solvent B followed by a 5 minute flowof 100% solvent B. The gradient was followed by a 2 min return to 40%solvent B. (B) Using a 20×50 mm column at 20 mL/min. The mobile phaseused was a mixture of solvent A (H₂O/0.1% TFA) and solvent B (ACN/0.1%TFA) with a 10 min gradient from 5% to 100% solvent B. The gradient isfollowed by a 2 min return to 5% ACN.

Proton NMR Spectra:

Unless otherwise indicated, all ¹H NMR spectra were run on a Varianseries Mercury 300 MHz instrument or a Bruker series 400 MHz instrument.Where so characterized, all observed protons are reported asparts-per-million (ppm) downfield from tetramethylsilane (TMS) or otherinternal reference in the appropriate solvent indicated.

Mass Spectra (MS)

Unless otherwise indicated, all mass spectral data for startingmaterials, intermediates and/or exemplary compounds are reported asmass/charge (m/z), having an (M+H⁺) molecular ion. The molecular ionreported was obtained by electrospray detection method. Compounds havingan isotopic atom, such as bromine and the like, are reported accordingto the detected isotopic pattern, as appreciated by those skilled in theart.

Example 1 (via Method A)

Synthesis of3-(1-(2-chlorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4b]pyridin-5-yl-5-fluoro-4-methylbenzamide Step 1A: Synthesis of5-Amino-1-(2-chlorophenyl)-1H-pyrazole-4-carbaldehyde

At RT, 2-(ethoxymethylene)malononitrile (5.77 g, 47.2 mmol) was added inportions to a stirred suspension of 1-(2-chlorophenyl)hydrazinehydrochloride (8.05 g, 45.0 mmol) and TEA (6.58 ml, 47.2 mmol) inabsolute EtOH (56 mL). The mixture was heated to reflux for 1 h. Thevolatile solvents were removed under reduced pressure. The brown residewas dissolved in EtOAc, washed with water followed by saturated NaHCO₃solution. The organic layer was dried over sodium sulfate, filtered, andconcentrated under reduced pressure to obtain5-amino-1-(2-chlorophenyl)-1H-pyrazole-4-carbonitrile as a rustycrystalline solid. MS (ESI, pos.ion) m/z: 219.0 (M+1).

Step 1B: To a solution of5-amino-1-(2-chlorophenyl)-1H-pyrazole-4-carbonitrile (2.0 g, 9.1 mmol)in glacial acetic acid (12.0 mL) was added Raney 2400 Nickel (1.1 g, 18mmol). The mixture was hydrogenated at RT with a balloon overnight. Thereaction mixture was filtered through a short plug of Celite, washingwith water then wet EtOAc. The water layer was separated and extractedwith EtOAc. The combined EtOAc layers were washed with 1.0 N NaOHfollowed by brine, dried over MgSO₄, filtered and concentrated. Thebrown residue was loaded on an ISCO 40 g column (eluted with 25-65%EtOAc in Hexanes) to afford the title compound,5-amino-1-(2-chlorophenyl)-1H-pyrazole-4-carbaldehyde, as a tancrystalline solid. MS (ESI, pos.ion) m/z: 220.0 (M+1).

Step 2: Synthesis of1-(2-Chlorophenyl)-1H-pyrazolo[3,4-b]pyridin-6(7H)-one

At −35° C., KHMDS (8.03 mL of 0.5 M in toluene, 4.01 mmol) was added toa slurry of methyl p,p-bis(2,2,2-trifluoroethyl)-phosphonoacetate (1.21g, 3.82 mmol) and 18-crown-6 (506 mg, 1.91 mmol) in 3.0 mL of THF. Afterthe resulting mixture was stirred at −35° C. for 10 min, a solution of5-amino-1-(2-chlorophenyl)-1H-pyrazole-4-carbaldehyde (424 mg, 1.91mmol) in THF (1.5 mL+1.5 mL rinsing) was added in via a syringe. Thereaction mixture was slowly warmed to RT overnight, quenched withsaturated NH₄Cl, and extracted with EtOAc twice. The combined EtOAclayers were dried and concentrated to dryness. The resulting brownresidue in THF (3.0 mL) at RT was treated with KHMDS (12 mL of 0.5 M intoluene, 6.0 mmol) and heated at 70° C. in an oil bath for 3 h. Afterthe reaction mixture was cooled to RT, it was treated with saturatedNH₄Cl, and extracted with EtOAc twice. The combined EtOAc layers weredried and concentrated. The brown residue was loaded on an ISCO 12 gcolumn (eluted with 25-65% EtOAc in Hexanes) to give the title compound(352 mg) as a yellow amorphous solid. MS (ESI, pos.ion) m/z: 246.0(M+1).

Step 3: Synthesis of1-(2-Chlorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one

At RT, 1-(2-chlorophenyl)-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (542 mg,2.20 mmol) in 4.0 mL of DMF was treated with anhydrous potassiumcarbonate (610 mg, 4.40 mmol) followed by iodomethane (0.2 mL, 3.21mol). After the mixture was stirred at RT overnight, it was filteredthrough a fritted funnel, and rinsed with EtOAc. The filtrate wasconcentrated and the residue was purified on an ISCO 40 g column (elutedwith 25-90% EtOAc in Hexanes) to provide: 1)1-(2-chlorophenyl)-6-methoxy-1H-pyrazolo[3,4-b]pyridine (150 mg) as ayellow thick oil, MS (ESI, pos.ion) m/z: 260.1 (M+1); 2)1-(2-chlorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (320 mg)as a light yellow crystalline solid, MS (ESI, pos.ion) m/z: 260.1 (M+1).

Step 4: Synthesis of5-bromo-1-(2-chlorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one

At RT, bromine (206 mg, 1.29 mmol) was added to a solution of12-chlorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (319 mg,1.23 mmol) in 1.5 mL of glacial acetic acid. After stirring at RT for 30min, it was diluted with water and stirred for 5 min. The precipitatedwhite solid was filtered off and rinsed with water, collected and driedto afford5-bromo-1-(2-chlorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one(323 mg). The filtrate was extracted three times with EtOAc. Thecombined EtOAc layers were washed with 2 N NaOH followed by brine, driedand concentrated to afford additional5-bromo-1-(2-chlorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one(82 mg). The crude material was used without further purification. MS(ESI, pos.ion) m/z: 338.0/340.0 (M+1).

Step 5: Synthesis of3-(1-(2-chlorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-5-fluoro-4-methylbenzamide

A mixture of3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(118 mg, 422 μmol),5-bromo-1-(2-chlorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one(130 mg, 384 μmol), Pd(PPh₃)₄ (0.016 mmol, 19 mg), and sodium carbonate(2 M) (0.576 ml, 1.15 μmol) in 2.0 mL of dioxane in a sealed tube washeated in a microwave at 125° C. for 25 min. The mixture was treatedwith 2 mL of 1 N NaOH solution, extracted with 2×5 mL of EtOAc. Thecombined organic phases were washed with 2 mL of brine, dried andconcentrated. The brown residue was loaded on an ISCO 12 g column(eluting with a gradient of 1-6% MeOH in DCM) to provide the titlecompound (140 mg) as an off white crystalline solid. MS (ESI, pos.ion)m/z: 411.2 (M+1).

Example 2 (via Method B)

Synthesis ofN-cyclopropyl-3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-5-fluoro-4-methylbenzamideStep 1: Synthesis of Ethyl1-(2,6-difluorophenyl)-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

In a 500 mL round-bottomed flask was added5-amino-1-(2,6-difluorophenyl)-1H-pyrazole-4-carbaldehyde (7.77 g, 35mmol; prepared in a fashion similar to that described for5-amino-1-(2-chlorophenyl)-1H-pyrazole-4-carbaldehyde in Example 1above) followed by ethanol (100 ml, 35 mmol). To the solution was addeddiethyl malonate (11 ml, 70 mmol) and piperidine (3.4 ml, 35 mmol) andthe mixture was heated to 75° C. overnight. The reaction mixture wasconcentrated under reduced pressure and the brown residue was treatedwith 200 mL of a 1:1 solution of EtOAc:Hexanes. The precipitated solidwas then filtered through a sintered glass frit and rinsed with hexanes.It was dried under high vacuum to afford the title compound (11.13 g,100% yield) as a beige crystalline solid. MS (ESI, pos.ion) m/z: 306.0(M+1).

Step 2:5-Bromo-1-(2,6-difluorophenyl)-1H-pyrazolo[3,4-b]pyridin-6(7H)-one

Ethyl1-(2,6-difluorophenyl)-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridine-5-carboxylate(9.40 g, 0.29 mmol) was treated with 80 mL CH₃CN and 80 mL water andlithium hydroxide monohydrate (3.10 g, 74 mmol). The resultingsuspension was then heated to 90° C. for 1 h. The solution was allowedto cool to 35° C. and treated with N-bromosuccimide (5.20 g, 29 mmol) inone portion. It was allowed to stir for 1 h at RT then treated withanother equiv. of N-bromosuccimide (5.20 g, 29 mmol) in one portion.After stirring for an additional 1 h at RT, it was treated with asaturated solution of NaHCO₃ and extracted with 2×150 mL EtOAc. Thecombined organic solution was washed with brine, dried over MgSO₄,filtered and concentrated to afford the title compound (8.31 g) as anorange foam in ca. 90% purity. No further purification was carried outprior to use in the next step. MS (ESI, pos.ion) m/z: 326.0/327.9 (M+1).For a related reference, see: Chowdhury, S.; Roy, S. J. Org. Chem. 1997,62, 199-200.

Step 3:5-Bromo-1-(2,6-difluorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one

5-Bromo-1-(2,6-difluorophenyl)-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (11.3g, 34.7 mmol) in DME (78 mL) and DMF (7.7 mL) was cooled to 0° C. underargon. NaH (1.24 g of 95% wt., 49 mmol) was then added in small portionsand the solution was allowed to stir at 0° C. for 10 min. Finely groundlithium bromide (8.83 g, 102 mmol) was then added and the solutionstirred at RT for 20 min at which point MeI (4.37 ml, 68.9 mmol) wasadded. The suspension was heated at 40° C. for 16 h then cooled to RT.The reaction mixture was quenched with water and extracted with EtOAc(3×100 mL). The combined organic solution was washed with 2×50 mL brine,dried over MgSO₄, filtered concentrated. The resulting crude solid wasthen suspended in 300 mL of 1:1 solution of EtOAc:Hexanes with stirringover 30 min. The solution was then allowed to precipitate in the freezerfor 2 h. The resulting solid was then collected by filtration washingwith MTBE affording5-bromo-1-(2,6-difluorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one(5.27 g) in >95% purity as a beige solid. The mother liquor was thenconcentrated to ca. 15 ml in vacuo (rotary evaporator) and treated with50 mL of MTBE and again chilled in the freezer overnight. The resultingsolid was collected by filtration and washing with MTBE to afford asecond crop of5-bromo-1-(2,6-difluorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one(1.54 g) in ca. 95% purity. MS (ESI, pos.ion) m/z: 340.0/342.0 (M+1).For a related reference, see: Liu, H.; Ko, S.-B.; Josien, H.; Curran, D.P. Tetrahedron Lett. 1995, 36, 8917-8920.

Step 4:N-cyclopropyl-3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-5-fluoro-4-methylbenzamide

A mixture of5-bromo-1-(2,6-difluorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one(110 mg, 0.32 mmol),N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(122 mg, 0.38 mmol) and 15 mg of Pd(PPh₃)₄ in 2.0 mL dioxane and 0.8 mLof 1 M Na₂CO₃ in a sealed glass tube was heated at 130° C. for 30 min.The reaction mixture was diluted in EtOAc, washed with 1 N NaOHsolution. The organic phase was dried over MgSO₄, filtered andconcentrated. Purification of the brown residue on an ISCO 12 g column(40-80% EtOAc in Hexanes) afforded the title compound (96 mg) as an offwhite amorphous solid. MS (ESI, pos.ion) m/z: 453.1 (M+1).

Example 3 (via Method D)

Synthesis of3-(1-(2,6-Difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-5-fluoro-N-(isoxazol-3-yl)-4-methylbenzamideStep 1:3-(1-(2,6-Difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-5-fluoro-4-methylbenzoicacid

In a 25 mL sealed glass tube, a mixture oftetrakis(triphenylphosphine)palladium(0) (42 mg, 37 μmol),3-borono-5-fluoro-4-methylbenzoic acid (218 mg, 1101 μmol), and5-bromo-1-(2,6-difluorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one(312 mg, 917 μmol) in 4.6 mL of dioxane and 1.0 M solution of sodiumcarbonate (2.3 mL, 2.3 mmol) was heated in a microwave at 130° C. for 30min. The reaction mixture was treated with 15 mL of ether and washedwith 5 mL of 2 N NaOH, The ether layer was discarded. The aqueousextracts were acidified to pH 4 with 5 N HCl and extracted with 3×25 mLEtOAc. The combined EtOAc layers were dried over MgSO₄, filtered andconcentrated in vacuo (rotovap) affording the title compound (296 mg) asa viscous oil which solidified to an off-white amorphous solid undervacuum overnight. MS (ES, pos.ion) m/z: 414.0 (M+1).

Step 2:3-(1-(2,6-Difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl-5-fluoro-N-(isoxazol-3-yl)-4-methylbenzamide

In a 100 mL round-bottom flask was weighed3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-5-fluoro-4-methylbenzoicacid (295 mg, 0.714 mmol) followed by SOCl₂ (5.00 mL, 6.85 mmol) undernitrogen. It was heated to 95° C. for 3 h then cooled to RT and theexcess thionyl chloride removed in vacuo (rotovap). The residue was thentreated with pyridine (3.00 mL) at 0° C. and isoxazol-3-amine (1.00 mL,1.42 mmol) was added. It was heated at 45° C. for 2 h. The reactionmixture was then concentrated in vacuo (rotovap) and the crude residuewas dissolved in DCM, washed sequentially with water, 1 N NaOH andbrine. The DCM solution was dried and concentrated. The brown residuewas purified on the ISCO (40 g column, eluted with 20-80% EtOAc:Hexanes)affording the title compound (87.9 mg) as a white amorphous solid. MS(ESI, pos.ion) m/z: 480.0 (M+1).

Example 4 (via Method E)

Synthesis of5Bromo-1-isopropyl-7-methyl-1H-pyrazolo[3,4b]pyridin-6(7H)-one Step 1:5-Bromo-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one acetic acid adduct

1-Tert-butyl-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one was preparedin a fashion similar to that described for1-(2-fluorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (155 mg)as a light yellow crystalline solid (Example 1—step 3).

To a solution of1-tert-butyl-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (240 mg, 1.17mmol) in glacial AcOH (5.5 mL) at RT was added bromine (0.060 mL, 1169μmol) slowly. An orange suspension resulted and it was allowed to stirat RT for 1 h. 5.0 mL water was added, and the pH was adjusted to pH 6using 5 N NaOH, It was extracted with 2×50 mL EtOAc, dried over MgSO₄,filtered and concentrated in vacuo (rotovap) affording5-bromo-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one acetic acid adduct(305 mg) as a beige solid. MS (ESI, pos.ion) m/z: 227.9 (M+1) and 229.9(M+1). This crude product was used in the next step.

Step 2: 5-Bromo-1-isopropyl-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one

At RT, to a solution of5-bromo-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one acetic acid adduct(202 mg, 0.701 mmol) in THF (10 mL) was treated with potassium carbonate(290 mg, 2.10 mmol) and 2-iodopropane (0.50 mL, 5.0 mmol). It was heatedto reflux for 48 h. The reaction mixture was then treated with water andextracted 2×20 mL EtOAc, dried over MgSO₄, filtered and concentrated invacuo (rotovap). The crude residue was purified on the ISCO (12 gcolumn, 25-90% EtOAc:Hexanes) affording the title compound (88 mg) as awhite amorphous solid in >95% purity. MS (ESI, pos.ion) m/z: 270.0/272.0(M+1).

These detailed descriptions of Examples fall within the scope, and serveto exemplify the above-described General Synthetic Procedures which formpart of the invention. These detailed descriptions are not intended as arestriction on the scope of the invention.

The following Examples in Table 1 will further assist in understandingand appreciating the invention. The compounds of examples 6-34 were madein accordance with exemplary methods A, B, D and E which correspond toabove Examples 1-4, respectively, and more generally to schemes 1-4. Thecompound examples were named according to the ACD naming convention, asassociated with ISIS software. The mass spectral data is recorded M+H⁺,which is the positive ion as measured by an electrospray ionizationmethod. The biological assay data is provided for those exemplarycompounds in Table 1 which were tested in, and data calculated from, thehuman whole blood and cellular assays. Not every compound example wasrun in the assays at the time of filing of this application, andaccordingly no data is provided in the Table.

TABLE 1 WB TNF/IL8 p38a Ex. MS IC50 IC50 No Name (M + H+) Method (nM)(nM) 6 N-cyclopropyl-3-(7-ethyl-1-(2-fluorophenyl)- 449.2 A 1.2 2.56-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-5-fluoro-4-methylbenzamide 2N-cyclopropyl-3-(1-(2,6-difluorophenyl)-7- 453.0 B 1.5 1.8methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-5-fluoro-4-methylbenzamide 7N-cyclopropyl-3-(1-(2,6-difluorophenyl)-7- 435.1 B 1.3 2.5methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylbenzamide 83-(1-(2-chlorophenyl)-7-methyl-6-oxo-6,7- 451.1 A 2.5 2.3dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-cyclopropyl-5-fluoro-4-methylbenzamide 9 N-cyclopropyl-3-fluoro-5-(1-(2-435.1 A 1.7 2.2 fluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4- methylbenzamide 103-(1-(2,6-difluorophenyl)-7-methyl-6-oxo- 475.1 B 2.2 2.96,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methyl-N-(1-methyl-1H-pyrazol-5- yl)benzamide 11N-cyclopropyl-3-(1-(2,4-difluorophenyl)-7- 453.0 B 2.0 2.6methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-5-fluoro-4-methylbenzamide 123-(1-(2-chlorophenyl)-7-methyl-6-oxo-6,7- 433.2 A 8.2 1.8dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-N- cyclopropyl-4-methylbenzamide13 N-cyclopropyl-3-(1-(2,4-difluorophenyl)-7- 435.1 B 2.8 5.2methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylbenzamide 14N-cyclopropyl-4-methyl-3-(7-methyl-1-(2- 413.1 B 10.3 4.2methylphenyl)-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)benzamide 13-(1-(2-chlorophenyl)-7-methyl-6-oxo-6,7- 411.1 A 18.0 2.3dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-5- fluoro-4-methylbenzamide 15N-cyclopropyl-3-fluoro-4-methyl-5-(7- 431.1 B 1.7 5.2methyl-1-(2-methylphenyl)-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5- yl)benzamide 16N-(3-(1-(2,4-difluorophenyl)-7-methyl-6-oxo- 435.1 B 73.66,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylphenyl)cyclopropanecarboxamide 17N-cyclopropyl-3-fluoro-4-methyl-5-(7- 383.1 E 35.3methyl-1-(1-methylethyl)-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)benzamide 183-(1-(2,6-difluorophenyl)-7-methyl-6-oxo- 462 D 1.3 36,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-3-isoxazolyl-4-methylbenzamide 33-(1-(2,6-difluorophenyl)-7-methyl-6-oxo- 480.0 D 0.8 2.46,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-5-fluoro-N-3-isoxazolyl-4-methylbenzamide 19N-cyclopropyl-4-(1-(2,6-difluorophenyl)-7- 436.1 B 13.3 18methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4- b]pyridin-5-yl)-5-methyl-2-pyridinecarboxamide 20 4-chloro-N-cyclopropyl-3-(1-(2,6- 455.2 B 4.0 2.5difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)benzamide 213-(1-(2,6-difluorophenyl)-7-methyl-6-oxo- 455.1 B 26.3 76,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)- 5-fluoro-4-methyl-N-(1-methylethyl)benzamide 22 3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo- 427 B9.1 6.2 6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-5-fluoro-N,4-dimethylbenzamide 23N-cyclopropyl-3-(1-(2,5-difluorophenyl)-7- 453 B 1.3 3.9methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-5-fluoro-4-methylbenzamide 24N-cyclopropyl-3-(1-(2,5-difluorophenyl)-7- 435.1 B 2.3 6.2methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylbenzamide 253-(1-(2,5-difluorophenyl)-7-methyl-6-oxo- 449 B 24.1 1.16,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methyl-N-(1-methylcyclopropyl)benzamide 263-(1-(2,5-difluorophenyl)-7-methyl-6-oxo- 462 D 1.4 2.36,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-3-isoxazolyl-4-methylbenzamide 273-(1-(2,4-difluorophenyl)-7-methyl-6-oxo- 462 D 1.7 2.46,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-3-isoxazolyl-4-methylbenzamide 283-(1-(2,6-difluorophenyl)-7-methyl-6-oxo- 478 D 16.7 1.16,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methyl-N-1,3-thiazol-2-ylbenzamide 294-chloro-N-cyclopropyl-3-(1-(2,5- 455.2 B 13.6difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)benzamide 303-(1-(2,6-difluorophenyl)-7-methyl-6-oxo- 449 B 6.36,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methyl-N-(1-methylcyclopropyl)benzamide 313-(1-(2,6-difluorophenyl)-7-methyl-6-oxo- 413 A 1.6 16,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)- 5-fluoro-4-methylbenzamide

Example 32 (via Method F)

Synthesis ofN-cyclopropyl-3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4b]pyridin-5-yl-4(hydroxymethyl)benzamideStep 1A: Synthesis of methyl 3-bromo-4-(bromomethyl)benzoate

Methyl 3-bromo-4-methylbenzoate (6.56 g, 28.64 mmol), carbontetrachloride (100 mL), NBS (6.07 g, 34.10 mmol) and AIBN (150 mg, 0.91mmol) were heated at reflux for 18 h. The reaction mixture was cooledand diluted with DCM (200 mL) and water (100 ml) and washed with 5%NaHCO₃ saturated solution (50 mL), dried over MgSO₄, filtered andconcentrated under reduced pressure (rotary evaporator) affording anoily residue.

Step 1B: Synthesis of methyl 4-(acetoxymethyl)-3-bromobenzoate

The residue from above was treated with glacial AcOH (30 mL) and KOAc(4.00 g, 40.76 mmol) and heated to 100° C. for 18 h. The reactionmixture was treated with crushed ice, CHCl₃ (150 mL) and neutralizedwith 10 N NaOH and NaHCO₃ saturated solution. The organic layer wasseparated and dried over MgSO₄, filtered and concentrated. The cruderesidue was purified on the ISCO 80 g column (eluted with 0-10% EtOAc inhexanes) affording the title compound as a white crystalline solid. MS(ESI, pos.ion) m/z: 313.1 (M+26).

Step 2: Synthesis of methyl4-(acetoxymethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

Methyl 4-(acetoxymethyl)-3-bromobenzoate (215 mg, 749 μmol), Pd(dppf)Cl₂(55 mg, 75 mol), KOAc (169 mg, 1722 pmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(285 mg, 1123 μmol) and 1,4-dioxane (2.0 mL) were heated in a microwaveat 130° C. for 23 min. The crude reaction mixture was filtered through aplug of celite washing with EtOAc. The residue was purified on the ISCO40 g column (5-25% EtOAc in hexanes) affording the title compound as awhite solid. MS (ESI, pos.ion) m/z: 357.1 (M+Na⁺).

Step 3: Synthesis of3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-(hydroxymethyl)benzoicacid

Tetrakis(triphenylphosphine)palladium(0) (38 mg, 33 μmol),5-bromo-1-(2,6-difluorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one(373 mg, 1096 μmol), methyl4-(acetoxymethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(403 mg, 1206 μmol) were treated with 1,4-dioxane (5.4 mL) and 1 Maqueous Na₂CO₃ (2.74 mL, 2741 μmol) under argon and heated in amicrowave at 130° C. for 30 min. The reaction mixture was treated withEtOAc (20 mL) and extracted with 1N NaOH (2×15 mL). The pH was adjustedto ca. pH 6 with 5N HCl and extracted with DCM (3×20 mL), dried overMgSO₄, filtered and concentrated affording the title compound (186 mg)as a yellow tar. The crude residue was used in the next step withoutfurther purification. MS (ESI, pos.ion) m/z: 412.1 (M+1).

Step 4: Synthesis ofN-cyclopropyl-3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-(hydroxymethyl)benzamide

3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-(hydroxymethyl)benzoicacid (310 mg, 754 μmol) was treated with cyclopropanamine (0.21 mL, 3014μmol) and HATU (430 mg, 1130 μmol) in THF (5.00 mL) under nitrogen andallowed to stir at RT. After 2 h the reaction was quenched by theaddition of 1N NaOH (10 mL). The reaction mixture was extracted withEtOAc (2×25 mL), dried over MgSO₄, filtered and concentrated. The cruderesidue was purified on the ISCO 12 g column (70-100% EtOAc in hexanes)affording the title compound as an amorphous white solid. MS (ESI,pos.ion) m/z: 451.1 (M+1).

Example 33 (via Method G)

Synthesis of4-chloro-3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4b]pyridin-5-yl)benzonitrileStep 1: Synthesis of 3-Bromo-4-chlorobenzenamine

A mixture of 2-bromo-1-chloro-4-nitrobenzene (1.57 g, 6.6 mmol) and 10%palladium on charcoal (297 mg, 2.8 mmol) in EtOAc (50 mL) was stirredunder an atmosphere of hydrogen (balloon) for 4 h. The reaction mixturewas filtered through a pad of celite washing with EtOAc. The EtOAc wasremoved under reduced pressure affording the title compound as brown oilwhich solidified upon standing. It was used in the next step withoutfurther purification. MS (ESI, pos.ion) m/z: 206.0/208.0 (M+1).

Step 2A: Synthesis of tert-Butyl 3-bromo-4-chlorophenylcarbamate

Boc₂O (852 mg, 3.90 mmol) and 3-bromo-4-chlorobenzenamine (733 mg, 3.55mmol) in THF (10 mL) were cooled in an ice bath and treated with NaH(102 mg, 4.26 mmol). It was stirred at 0° C. for 30 min then at RT for 2h. The flask was fitted with a condenser and heated to 75° C. for 16 h.The solution was then cooled to RT, treated with brine (50 mL) andextracted with EtOAc (2×25 mL), dried over MgSO₄, filtered andconcentrated. The crude residue was then purified on the ISCO 40 gcolumn (0-25% EtOAc in hexanes) affording the title compound (813 mg) asa colorless crystalline solid. MS (ESI, pos.ion) m/z: 249.9/252.0(M-t-Bu+1).

Step 2B: Synthesis oftert-Butyl-4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate

A mixture of Pd(dppf)Cl₂ (126 mg, 0.17 mmol), KOAc (390 mg, 3.97 mmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(658 mg, 2.59 mmol) and tert-butyl 3-bromo-4-chlorophenylcarbamate (530mg, 1.73 mmol) in 1,4-dioxane (5 mL) was heated in a microwave at 130°C. for 25 min. The crude reaction mixture was filtered through a pad ofcelite, and rinsed with EtOAc. The filtrate was concentrated and thecrude residue was purified on the ISCO 40 g column (0-30% EtOAc inhexanes) to afford the title compound as a light yellow oil thatcrystallized upon standing. MS (ESI, pos.ion) m/z: 376.1 (M+Na⁺).

Step 3: Synthesis of tert-Butyl4-chloro-3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)phenylcarbamate

A mixture of tetrakis(triphenylphosphine)palladium(0) (42 mg, 0.037mmol),5-bromo-1-(2,6-difluorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7,H)-one(415 mg, 1.22 mmol) and tert-butyl4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate(475 mg, 1.3 mmol) in 1,4-dioxane (5 mL) and 1M aqueous solution ofNa₂CO₃ (2.44 mL, 2.44 mmol) was heated in a microwave at 130° C. for 35min. The reaction mixture was treated with brine (20 mL) and extractedwith EtOAc (2×25 mL). The organic extracts were dried over MgSO₄,filtered and concentrated. The crude residue was used in the subsequentstep without further purification. MS (ESI, pos.ion) m/z: 487.1 (M+1).

Step 4A: Synthesis of5-(5-Amino-2-chlorophenyl)-1-(2,6-difluorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one

The crude residue from above in DCM (15 mL) at RT was treated with TFA(0.5 mL). The reaction mixture was stirred at RT for 1 h then 45° C. inan oil bath for 2 h. The volatiles were removed under reduced pressure.The remaining brown residue was dissolved in DCM, and neutralized with asaturated solution of NaHCO₃. The DCM solution was dried over MgSO₄,filtered and concentrated. The crude residue was purified on the ISCO 40g column (30-90% EtOAc in hexanes) affording the title compound as anoff-white amorphous solid. MS (ESI, pos.ion) m/z: 387.0 (M+1).

Step 4B: Synthesis of5-(2-Chloro-5-iodophenyl)-1-(2,6-difluorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one

At RT, a mixture of5-(5-amino-2-chlorophenyl)-1-(2,6-difluorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one(230 mg, 0.59 mmol), iodine (151 mg, 0.59 mmol), copper(I) iodide (34mg, 0.18 mmol) and cesium iodide (154 mg, 0.59 mmol) in DME (4.40 mL)was treated with isoamyl nitrite (0.48 mL, 3.57 mmol) drop wise over 3min. The reaction mixture was stirred for 4 h, and filtered through apad of celite washing with EtOAc (100 mL). The organic layer was washedsequentially with ˜2% NH₄OH (20 mL), a solution of sodium thiosulfate(20 mL) and brine (20 mL), dried over MgSO₄, filtered and concentrated.The crude residue was purified on the ISCO 12 g column (10-60% EtOAc inhexanes) affording the title compound as a white crystalline solid. MS(ESI, pos.ion) m/z: 497.9 (M+1).

Step 5: Synthesis of4-chloro-3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)benzonitrile

A mixture of5-(2-chloro-5-iodophenyl)-1-(2,6-difluorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one(60 mg, 0.12 mmol) and copper(I) cyanide (54 mg, 0.6 mmol) in DMF (1.5mL) were heated in a microwave at 140° C. for 1 h. LC-MS indicates ˜60%conversion to the desired product. Additional copper(I) cyanide (100 mg)was added and the reaction mixture was heated for another 1 h in themicrowave at 140° C. The reaction mixture was diluted in DCM (20 mL),washed with brine (2×15 mL), dried over MgSO₄, filtered andconcentrated. The crude residue was purified on the ISCO 12 g column(15-50% EtOAc in hexanes) affording the title compound as a whiteamorphous solid. MS (ESI, pos.ion) m/z: 397.0 (M+1).

Example 34 (via Method H)

Synthesis ofN-cyclopropyl-3-(1-(2,6-difluorophenyl)-7-methyl-6-thioxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl-4-methylbenzamideStep 1: Synthesis of5-Bromo-1-(2,6-difluorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridine-6(7H)-thione

A mixture of Lawesson's reagent (297 mg, 0.73 mmol) and5-bromo-1-(2,6-difluorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one(125 mg, 0.68 mmol) in toluene (8 mL) was heated to 125° C. for 15 h.The solvent was removed under reduced pressure (rotary evaporator) andthe crude residue was purified on the ISCO 40 g column (5-40% EtOAc inhexanes) affording the title compound (101.6 mg) as a bright yellowcrystalline solid. MS (ESI, pos.ion) m/z: 355.9/357.9 (M+1).

Step 2:N-Cyclopropyl-3-(1-(2,6-difluorophenyl)-7-methyl-6-thioxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylbenzamide

The title compound was prepared by a method similar to that described inExample 1, step 5 (Method A), starting from the1-cyclopropyl-3-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ureaand5-bromo-1-(2,6-difluorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridine-6(7H)-thione.MS (ESI, pos.ion) m/z: 451.1 (M+1).

Example 35 (via Method I)

Synthesis ofN-cyclopropyl-3-(1-(2,4-difluorophenyl)-7-(2,3-dihydroxypropyl)-6-oxo-6,7-dihydro-1H-pyrazolo[3,4b]pyridin-5-yl)-4-methylbenzamideStep 1: Synthesis of7-Allyl-5-bromo-1-(2,4-difluorophenyl)-1H-pyrazolo[3,4-b]pyridin-6(7H)-one

A solution of5-bromo-1-(2,4-difluorophenyl)-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (1.05g, 3.22 mmol) in DME (10 mL) and DMF (0.9 mL) at 0° C. was treated withNaH (116 mg, 4.8 mmol). After stirring for 20 min at RT, lithium bromide(1.67 g, 19.32 m mol) was added and the reaction mixture was allowed tostir for 1 h at RT before addition of 3-bromoprop-1-ene (0.28 ml, 3.22mmol). The mixture was allowed to stir at 40° C. for 18 h. The mixturewas quenched with brine and extracted with 2×30 mL EtOAc. The combinedEtOAc layers were washed with brine, dried and concentrated.Purification on the ISCO (40 g column, 10-80% EtOAc in Hexanes) afforded7-allyl-5-bromo-1-(2,4-difluorophenyl)-1H-pyrazolo[3,4-b]pyridin-6(7H)-oneas a tan amorphous solid. MS (ESI, pos.ion) m/z: 365.9/367.9 (M+1).

Step 2: Synthesis of5-Bromo-1-(2,4-difluorophenyl)-7-(2,3-dihydroxypropyl)-1H-pyrazolo[3,4-b]pyridin-6(7H)-one

A solution of7-allyl-5-bromo-1-(2,4-difluorophenyl)-1H-pyrazolo[3,4-b]pyridin-6(7H)-one(265 mg, 0.724 mmol) in tert-BuOH (5 mL) and water (5 mL) at RT wastreated with 4-methylmorpholine N-oxide (127 mg, 1.09 mmol) andpotassium osmate dihydrate (10 mg, 0.027 mmol). The resulting mixturewas allowed to stir for 16 h at RT, then diluted with an aqueoussolution of sodium sulfite (10 mL) and extracted with EtOAc (3×25 mL).The organic extracts were dried over MgSO₄, filtered and concentrated.The crude residue was purified on the ISCO 12 g column (0-5% MeOH:DCM)affording the title compound as a white amorphous solid. MS (ESI,pos.ion) m/z: 399.0/401.0 (M+1).

Step 3: Synthesis ofN-cyclopropyl-3-(1-(2,4-difluorophenyl)-7-(2,3-dihydroxypropyl)-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylbenzamide

The title compound was prepared by a method similar to that described inExample 1, step 5 (Method A), starting from the1-cyclopropyl-3-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ureaand5-bromo-1-(2,4-difluorophenyl)-7-(2,3-dihydroxypropyl)-1H-pyrazolo[3,4-b]pyridin-6(7H)-one.MS (ESI, pos.ion) m/z: 495.1 (M+1).

Example 36

Synthesis of1-Cyclopropyl-3-(3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylphenyl)ureaStep 1: Synthesis of1-cyclopropyl-3-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea

A mixture of CDI (254 mg, 1.57 mmol) and4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenamine (332mg, 1.42 mmol) under nitrogen was treated with THF (10 mL) and heated to50° C. for 45 min. The solution was then cooled to RT and treated withcyclopropylamine (113 μl, 1.64 mmol) and again heated to 40° C. for 11h. The volatiles were then removed in vacuo (rotary evaporator) and thecrude solid was purified on the ISCO 40 g column (15-70% EtOAc inhexanes) affording the title compound as a white amorphous solid. MS(ESI, pos.ion) m/z: 317.2 (M+1).

Step 2: Synthesis of1-cyclopropyl-3-(3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylphenyl)urea

The title compound was prepared by a method similar to that described inExample 1, step 5 (Method A), starting from the1-cyclopropyl-3-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ureaand5-bromo-1-(2,6-difluorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one.MS (ESI, pos.ion) m/z: 317.2 (M+1).

The following Examples in Table 2 will further assist in understandingand appreciating the invention. The compounds of examples 37-53 weremade in accordance with exemplary methods A, B and D-I, which correspondto Examples 1-4 and 32-35 above, respectively, and named according tothe ACD naming convention, as associated with ISIS software. The massspectral data is recorded M+H⁺, which is the positive ion as measured byan electrospray ionization method. The biological assay data is providedfor those exemplary compounds in Table 2 which were tested in, and datacalculated from, the human whole blood and p38α cellular assays. Notevery compound example was run in these assays at the time of filing ofthis application, and accordingly no data is provided in the Table.

TABLE 2 WB TNF/IL8 p38a Ex. MS IC50 IC50 No. Name (M + H+) Method (nM)(nM) 37 5-(5-amino-2-methylphenyl)-1-(2,4- 367 G 326difluorophenyl)-7-methyl-1,7-dihydro-6H- pyrazolo[3,4-b]pyridin-6-one 383-(1-(2,6-difluorophenyl)-7-methyl-6-oxo- 396.1 B 2500 7046,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)- 4-methylbenzoic acid 395-(5-amino-2-methylphenyl)-1-(2,6- 367 G 60difluorophenyl)-7-methyl-1,7-dihydro-6H- pyrazolo[3,4-b]pyridin-6-one 401-(2,6-difluorophenyl)-5-(5-iodo-2- 478 G 2500methylphenyl)-7-methyl-1,7-dihydro-6H- pyrazolo[3,4-b]pyridin-6-one 413-(1-(2,4-difluorophenyl)-7-methyl-6-oxo- 396 B 2500 10006,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)- 4-methylbenzoic acid 424-chloro-3-(1-(2,6-difluorophenyl)-7-methyl- 416.0 B 25006-oxo-6,7-dihydro-1H-pyrazolo[3,4- b]pyridin-5-yl)benzoic acid 431-(2,4-difluorophenyl)-5-(5-iodo-2- 478 G 2500methylphenyl)-7-methyl-1,7-dihydro-6H- pyrazolo[3,4-b]pyridin-6-one 443-(1-(2,6-difluorophenyl)-7-methyl-6-oxo- 395 B 5.4 3.46,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)- 4-methylbenzamide 453-(1-(2,6-difluorophenyl)-7-methyl-6-oxo- 569.1 D 2500 7.86,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methyl-N-(2-(methyloxy)-5- (trifluoromethyl)phenyl)benzamide 32N-cyclopropyl-3-(1-(2,6-difluorophenyl)-7- 451.1 F 16 21methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-(hydroxymethyl)benzamide 46N-cyclopropyl-3-(1-(2,4-difluorophenyl)-7- 449.1 B 2.5 4.9ethyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylbenzamide 333-(1-(2,6-difluorophenyl)-7-methyl-6-oxo- 377.1 G 25006,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)- 4-methylbenzonitrile 34N-cyclopropyl-3-(1-(2,6-difluorophenyl)-7- 451.1 H 4.4 2.6methyl-6-thioxo-6,7-dihydro-1H- pyrazolo[3,4-b]pyridin-5-yl)-4-methylbenzamide 47 N-cyclopropyl-3-(1-(cyclopropylsulfonyl)-7- 427.1 E662 methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylbenzamide 48 5-(5-amino-2-chlorophenyl)-1-(2,6-387 G 327 difluorophenyl)-7-methyl-1,7-dihydro-6H-pyrazolo[3,4-b]pyridin-6-one 49 5-(2-chloro-5-iodophenyl)-1-(2,6- 497.9G difluorophenyl)-7-methyl-1,7-dihydro-6H- pyrazolo[3,4-b]pyridin-6-one50 4-chloro-3-(1-(2,6-difluorophenyl)-7-methyl- 397 G 25006-oxo-6,7-dihydro-1H-pyrazolo[3,4- b]pyridin-5-yl)benzonitrile 51N-cyclopropyl-3-(1-(2,4-difluorophenyl)-7- 581.3 H 225methyl-6-thioxo-6,7-dihydro-1H- pyrazolo[3,4-b]pyridin-5-yl)-4-methylbenzenecarbothioamide 35N-cyclopropyl-3-(1-(2,4-difluorophenyl)-7- 495.1 I 22 34(2,3-dihydroxypropyl)-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4- methylbenzamide 52N-cyclopropyl-3-(1-(4-fluorophenyl)-7- 417.1 B 7.2 6.1methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylbenzamide 53 4-chloro-N-cyclopropyl-3-(1-(4-437.1 B 27 6 fluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)benzamide 361-cyclopropyl-3-(3-(1-(2,6-difluorophenyl)-7- 450.1 A 261methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylphenyl)urea

The following compounds in Table 3 are additional representativeexamples of Formula I as provided by the present invention.

TABLE 3

Ex. No. R¹ R⁴ R⁶ R⁵ R⁷ or R⁸ 54 3,5-difluoro-Ph —CH₂CH₃— H —C(O)NH—oxazolyl 55 morpholine —CH₃— H —C(O)NH— methyl or cyclopropyl 56piperazine —CH₂CH₃— H —C(O)NH— methyl or cyclopropyl 57 piperidine —CH₃—H —C(O)NH— methyl or cyclopropyl 58 phenyl —CH₃— F —C(O)NH— methyl orcyclopropyl 59 m-CH₃-phenyl- —CH₂CH₃— Cl —C(O)NH— methyl or cyclopropyl60 m-Cl-phenyl- —CH₂CH₃— OCH₃ —C(O)NH— methyl or cyclopropyl 613,5-difluoro-Ph —CH₂CH₃— H —C(O)NH— isoxazolyl 62 morpholine —CH₃— H—C(O)NH— pyrazolyl 63 piperazine —CH₂CH₃— H —C(O)NH— imidazolyl 64piperidine —CH₃— H —C(O)NH— triazolyl 65 phenyl —CH₃— F —C(O)NH—tetrazolyl 66 m-CH₃-phenyl- —CH₂CH₃— Cl —C(O)NH— thioazolyl 672-cl-phenyl —CH₂CH₃— OCH₃ —C(O)NH— isothiazolyl 68 2-CH₃-phenyl —CH₂CH₃—H —NHC(O)— phenyl 69 4-CH₃-phenyl —CH₃— H —NHC(O)— cyclopropyl 704-cl-phenyl —CH₂CH₃— di-F —NHC(O)— ethyl 71 3-cl-phenyl —CH₃— di-Cl—NHC(O)— propyl 72 3-CH₃-phenyl —CH₃— OCH₃ —NHC(O)— butyl 73 2-thiophene—CH₂CH₃— CF₃ —NHC(O)— isopropryl 74 3-thiophene —CH₃— OCF₃ —NHC(O)—isobutyl 75 2-pyridine —CH₂CH₃— OH —NHC(O)— cyclopentyl 76 1-morpholinyl—(CH₂)₂CH₃— F —C(O)NH— ethyl 77 1-piperazinyl —CH₃— Cl —C(O)NH— ethyl 781-piperidinyl —CH₂CH₃— OCH₃ —C(O)NH— ethyl 79 3,5-difluoro-Ph —CH₃— F—C(O)NH— ethyl 80 3-cl-phenyl —CH₂CH₃— Cl —C(O)NH— ethyl 81 3-CH₃-phenyl—CH₃— OCH₃ —C(O)NH— ethyl 82 2-thiophene —CH₂CH₃— H —C(O)NH— ethyl 83phenyl —CH₃— —NHCH₃ —NH— isoxazolyl 84 3-amido-1-pyrrolidinyl —CH₃— H—NH— pyrazolyl 85 3-amido-1-piperidinyl —CH₂CH₃— H —NH— imidazolyl 864-amido-1-piperidinyl —CH₃— F —NH— triazolyl 87 4N-CH₃-1-piperizinyl—CH₂CH₃— Cl —C(O)— tetrazolyl 88 2-cl-phenyl —(CH₂)₂CH₃— OCH₃ —C(O)—thioazolyl 89 2-CH₃-phenyl —CH₃— F —C(O)— isothiazolyl 90 4-CH₃-phenyl—CH₂CH₃— Cl —C(O)— phenyl 91 4-cl-phenyl —CH₂CH₃— OCH₃ —C(O)NH—cyclopropyl 92 3-cl-phenyl —CH₃— F —C(O)NH— ethyl 93 3-CH₃-phenyl —CH₃——NHCH₃ —C(O)NH— propyl 94 2-thiophene —CH₂CH₃— H —C(O)NH— ethyl 953-thiophene —(CH₂)₂CH₃— H —C(O)NH— ethyl 96 2-pyridine —CH₃— F —C(O)NH—ethyl 97 1-morpholinyl —CH₂CH₃— Cl —C(O)NH— cyclopropyl 98 1-piperazinyl—CH₂CH₃— CN —NHC(O)— propyl 99 1-piperidinyl —CH₃— CF₃ —NHC(O)—cyclopropyl 100 cyclohexyl-N— —CH₃— OH —NHC(O)— cyclopropyl 101morpholine-(CH₂)₂—N— —CH₂CH₃— NHCH₃ —NHC(O)— propyl 102 (CH₃)₂N—(CH₂)₂——(CH₂)₂CH₃— H —NHC(O)— propyl 103 (C₂H₅)₂N—(CH₂)₂— —CH₃— acetyl —NHC(O)—cyclopropyl 104 3-OH-1-pyrrolidinyl —CH₂CH₃— H —NHC(O)— propyl 105—CH₂CH₃— —CH₂CH₃— H —NHC(O)— propyl 106 —(CH₂)₂CH₃— —CH₂CH₃— acetyl—C(O)NH— isoxazolyl 107 —CH₃— —(CH₂)₂CH₃— H —C(O)NH— pyrazolyl 1084N-CH₃-1-piperizinyl —CH₃— H —C(O)NH— imidazolyl 109 2-cl-phenyl—CH₂CH₃— H —C(O)NH— triazolyl 110 2-CH₃-phenyl —CH₂CH₃— H —C(O)NH—tetrazolyl 111 4-CH₃-phenyl —CH₃— CN —C(O)NH— thioazolyl 112 4-cl-phenyl—CH₃— H —S(O)₂NH— isothiazolyl 113 3-cl-phenyl —CH₂CH₃— H —NH— phenyl114 3-CH₃-phenyl —(CH₂)₂CH₃— H —NH— cyclopropyl 115 2-thiophene —CH₃— H—NH— ethyl 116 3-thiophene —CH₂CH₃— H —NH— propyl 117 2-pyridine—CH₂CH₃— H —C(O)— isoxazolyl 118 4-F-phenyl —CH₃— CH₃ —C(O)— pyrazolyl

The following compounds in Table 4 are additional representativeexamples of Formula II as provided by the present invention.

TABLE 4

Ex. No. R¹ Z R⁶ R⁵ R⁷ or R⁸ 119 3-thiophene isoxazolyl H —C(O)NH— Methylor cyclopropyl 120 2-pyridine pyrazolyl F —C(O)NH— Methyl or cyclopropyl121 1-morpholinyl imidazolyl Cl —C(O)NH— Methyl or cyclopropyl 1221-piperizinyl triazolyl Br —NHC(O)— Methyl or cyclopropyl 1231-piperidinyl tetrazolyl OH —NHC(O)— Methyl or cyclopropyl 124cyclohexyl-N- thioazolyl CN —NHC(O)— Methyl or cyclopropyl 125morpholine-(CH₂)₂—N— isothiazolyl H —NHC(O)— Methyl or cyclopropyl 126(CH₃)₂N—(CH₂)₂— oxazolyl H —NHC(O)— Methyl or cyclopropyl 127(C₂H₅)₂N—(CH₂)₂— pyrrole H —NHC(O)— Methyl or cyclopropyl 1283-OH-1-pyrrolidinyl pyridyl H —NHC(O)— Methyl or cyclopropyl 129—CH₂CH₃— pyrimidyl H —NHC(O)— Methyl or cyclopropyl 130 —(CH₂)₂CH₃—pyridinonyl H —C(O)NH— Methyl or cyclopropyl 131 —CH₃— oxazolyl H—C(O)NH— Methyl or cyclopropyl 132 4N-CH₃-1-piperizinyl isoxazolyl H—C(O)NH— Methyl or cyclopropyl 133 2-cl-phenyl 2-thiophene H —C(O)NH—Methyl or cyclopropyl 134 2-CH₃-phenyl 3-thiophene H —C(O)NH— Methyl orcyclopropyl 135 4-CH₃-phenyl 2-pyridine H —C(O)NH— Methyl or cyclopropyl136 4-cl-phenyl 3-pyridine H —S(O)₂NH— Methyl or cyclopropyl 1373-cl-phenyl pyrazolyl H —NH— Methyl or cyclopropyl 138 3-CH₃-phenylimidazolyl H —NH— Methyl or cyclopropyl 139 2-thiophene triazolyl H —NH—Methyl or cyclopropyl 140 3-thiophene tetrazolyl H —NH— ethyl 1412-pyridine thioazolyl H —C(O)— ethyl 142 4-F-phenyl isothiazolyl H—C(O)— ethyl 143 3-thiophene oxazolyl H —C(O)— ethyl 144morpholine-(CH₂)₂— isoxazolyl H —NH— ethyl 145 (CH₃)₂N—(CH₂)₂— pyrazolylH —NH— ethyl 146 (C₂H₅)₂N—(CH₂)₂— imidazolyl H —NH— cyclopropyl 1473-OH-1-pyrrolidinyl triazolyl H —NH— propyl 148 3-amido-1-pyrrolidinyltetrazolyl H —NH— cyclopropyl 149 3-amido-1-piperidinyl thioazolyl H—NH— cyclopropyl 150 4-amido-1-piperidinyl isothiazolyl H —NH— propyl151 4N-CH₃-1-piperizinyl oxazolyl H —NH— propyl 152 2-cl-phenyl pyrroleH —NH— cyclopropyl 153 2-CH₃-phenyl pyridyl H —NH— propyl 1544-CH₃-phenyl pyrimidyl H —NH— propyl 155 4-cl-phenyl pyridinonyl H —NH—isoxazolyl 156 3-cl-phenyl oxazolyl H —NH— pyrazolyl 157 3-CH₃-phenylisoxazolyl H —NH— imidazolyl 158 2-thiophene 2-thiophene H —NH—triazolyl 159 3-thiophene 3-thiophene H —NH— tetrazolyl 160 2-pyridine2-pyridine H —NH— thioazolyl 161 1-morpholinyl 3-pyridine H —NH—isothiazolyl 162 1-piperazinyl pyrazolyl H —NH— phenyl 163 1-piperidinylimidazolyl H —NH— cyclopropyl 164 cyclohexyl- triazolyl H —NH— ethyl 165morpholine-(CH₂)₂— tetrazolyl H —NH— propyl 166 (CH₃)₂N—(CH₂)₂—thioazolyl H —C(O)NH— isoxazolyl 167 (C₂H₅)₂N—(CH₂)₂— isothiazolyl H—C(O)NH— pyrazolyl 168 3-OH-1-pyrrolidinyl oxazolyl H —C(O)NH— ethyl 1693-amido-1-pyrrolidinyl isoxazolyl H —C(O)NH— ethyl 1703-amido-1-piperidinyl pyrazolyl H —NH— cyclopropyl 1714-amido-1-piperidinyl imidazolyl H —NH— propyl 172 4N-CH₃-1-piperizinylisoxazolyl H —NH— propyl 173 2-cl-phenyl pyrazolyl H —NH— propyl 1742-CH₃-phenyl imidazolyl H —NH— isopropyl 175 4-CH₃-phenyl triazolyl H—NH— propyl 176 4-cl-phenyl tetrazolyl H —NH— propyl 177 3-cl-phenylthioazolyl H —NH— isopropyl 178 3-CH₃-phenyl isothiazolyl H —NH— propyl179 2-thiophene oxazolyl H —NH— isopropyl 180 3-thiophene pyrrole H —NH—allyl 181 2-pyridine pyridyl H —NH— propyl 182 4-F-phenyl pyrimidyl CH₃—NH— cyclopropyl

While the examples and schemes described above provide processes forsynthesizing compounds, and intermediates thereof, of Formulas I, I-Band I-C, it should be appreciated that other methods may be utilized toprepare such compounds. Methods involving the use of protecting groupsmay be used. Particularly, if one or more functional groups, for examplecarboxy, hydroxy, amino, or mercapto groups, are or need to be protectedin preparing the compounds of the invention, because they are notintended to take part in a specific reaction or chemical transformation,various known conventional protecting groups may be used. For example,protecting groups typically utilized in the synthesis of natural andsynthetic compounds, including peptides, nucleic acids, derivativesthereof and sugars, having multiple reactive centers, chiral centers andother sites potentially susceptible to the reaction reagents and/orconditions, may be used.

The protecting groups may already be present in precursors and shouldprotect the functional groups concerned against unwanted secondaryreactions, such as acylations, etherifications, esterifications,oxidations, solvolysis, and similar reactions. It is a characteristic ofprotecting groups that they readily lend themselves, i.e. withoutundesired secondary reactions, to removal, typically accomplished bysolvolysis, reduction, photolysis or other methods of removal such as byenzyme activity, under conditions analogous to physiological conditions.It should also be appreciated that the protecting groups should not bepresent in the end-products. Persons of ordinary skill in the art know,or can easily establish, which protecting groups are suitable with thereactions described herein.

The protection of functional groups by protecting groups, the protectinggroups themselves, and their removal reactions (commonly referred to as“deprotection”) are described, for example, in standard reference works,such as J. F. W. McOmie, Protective Groups in Organic Chemistry, PlenumPress, London and New York (1973), in T. W. Greene, Protective Groups inOrganic Synthesis, Wiley, New York (1981), in The Peptides, Volume 3, E.Gross and J. Meienhofer editors, Academic Press, London and New York(1981), in Methoden der Organischen Chemie (Methods of OrganicChemistry), Houben Weyl, 4th edition, Volume 15/1, Georg Thieme Verlag,Stuttgart (1974), in H.-D. Jakubke and H, Jescheit, Aminosäuren,Peptide, Proteine (Amino Acids, Peptides, Proteins), Verlag Chemie,Weinheim, Deerfield Beach, and Basel (1982), and in Jochen Lehmann,Chemie der Kohlenhydrate: Monosaccharide und Derivate (Chemistry ofCarbohydrates: Monosaccharides and Derivatives), Georg Thieme Verlag,Stuttgart (1974).

Salts of a compound of the invention having a salt-forming group may beprepared in a conventional manner or manner known to persons skilled inthe art. For example, acid addition salts of compounds of the inventionmay be obtained by treatment with an acid or with a suitable anionexchange reagent. A salt with two acid molecules (for example adihalogenide) may also be converted into a salt with one acid moleculeper compound (for example a monohalogenide); this may be done by heatingto a melt, or for example by heating as a solid under a high vacuum atelevated temperature, for example from 50° C. to 170° C., one moleculeof the acid being expelled per molecule of the compound.

Acid salts can usually be converted to free-base compounds, e.g. bytreating the salt with suitable basic agents, for example with alkalimetal carbonates, alkali metal hydrogen carbonates, or alkali metalhydroxides, typically potassium carbonate or sodium hydroxide. Exemplarysalt forms and their preparation are described herein in the Definitionsection of the application.

All synthetic procedures described herein can be carried out under knownreaction conditions, advantageously under those described herein, eitherin the absence or in the presence (usually) of solvents or diluents. Asappreciated by those of ordinary skill in the art, the solvents shouldbe inert with respect to, and should be able to dissolve, the startingmaterials and other reagents used. Solvents should be able to partiallyor wholly solubilize the reactants in the absence or presence ofcatalysts, condensing agents or neutralizing agents, for example ionexchangers, typically cation exchangers for example in the H⁺ form. Theability of the solvent to allow and/or influence the progress or rate ofthe reaction is generally dependant on the type and properties of thesolvent(s), the reaction conditions including temperature, pressure,atmospheric conditions such as in an inert atmosphere under argon ornitrogen, and concentration, and of the reactants themselves.

Suitable solvents for conducting reactions to synthesize compounds ofthe invention include, without limitation, water; esters, includinglower alkyl-lower alkanoates, e.g., ethyl acetate; ethers includingaliphatic ethers, e.g., Et₂O and ethylene glycol dimethylether or cyclicethers, e.g., THF; liquid aromatic hydrocarbons, including benzene,toluene and xylene; alcohols, including MeOH, EtOH, 1-propanol, IPOH, n-and t-butanol; nitriles including CH₃CN; halogenated hydrocarbons,including CH₂Cl₂, —CHCl₃ and CCl₄; acid amides including DMF;sulfoxides, including DMSO; bases, including heterocyclic nitrogenbases, e.g. pyridine; carboxylic acids, including lower alkanecarboxylicacids, e.g., AcOH; inorganic acids including HCl, HBr, HF, H₂SO₄ and thelike; carboxylic acid anhydrides, including lower alkane acidanhydrides, e.g., acetic anhydride; cyclic, linear, or branchedhydrocarbons, including cyclohexane, hexane, pentane, isopentane and thelike, and mixtures of these solvents, such as purely organic solventcombinations, or water-containing solvent combinations e.g., aqueoussolutions. These solvents and solvent mixtures may also be used in“working-up” the reaction as well as in processing the reaction and/orisolating the reaction product(s), such as in chromatography.

The invention further encompasses “intermediate” compounds, includingstructures produced from the synthetic procedures described, whetherisolated or not, prior to obtaining the finally desired compound.Structures resulting from carrying out steps from a transient startingmaterial, structures resulting from divergence from the describedmethod(s) at any stage, and structures forming starting materials underthe reaction conditions are all “intermediates” included in theinvention. Further, structures produced by using starting materials inthe form of a reactive derivative or salt, or produced by a compoundobtainable by means of the process according to the invention andstructures resulting from processing the compounds of the invention insitu are also within the scope of the invention.

New starting materials and/or intermediates, as well as processes forthe preparation thereof, are likewise provided by this invention.Starting materials of the invention, are either known, commerciallyavailable, or can be synthesized in analogy to or according to methodsthat are known in the art. Many starting materials may be preparedaccording to known processes and, in particular, can be prepared usingprocesses described in the examples. In synthesizing starting materials,functional groups may be protected with suitable protecting groups whennecessary. Protecting groups, their introduction and removal aredescribed above.

In synthesizing a compound of formulas I, I-B and I-C according to adesired procedure, the steps may be performed in an order suitable toprepare the compound, including a procedure described herein or by analternate order of steps described herein, and may be preceded, orfollowed, by additional protection/deprotection steps as necessary. Theprocedures may further use appropriate reaction conditions, includinginert solvents, additional reagents, such as bases (e.g., LDA, DIEA,pyridine, K₂CO₃, and the like), catalysts, and salt forms of the above.The intermediates may be isolated or carried on in situ, with or withoutpurification. Purification methods are known in the art and include, forexample, crystallization, chromatography (liquid and gas phase, and thelike), extraction, distillation, trituration, reverse phase HPLC and thelike. Reactions conditions such as temperature, duration, pressure, andatmosphere (inert gas, ambient) are known in the art and may be adjustedas appropriate for the reaction. Synthetic chemistry transformations andprotecting group methodologies (protection and deprotection) useful insynthesizing the inhibitor compounds described herein are known in theart and include, for example, those such as described in R. Larock,Comprehensive Organic Transformations, VCH Publishers (1989); T. W.Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3^(rd)edition, John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser andFieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); A.Katritzky and A. Pozharski, Handbook of Heterocyclic Chemistry, 2^(nd)edition (2001); M. Bodanszky, A. Bodanszky, The Practice of PeptideSynthesis, Springer-Verlag, Berlin Heidelberg (1984); J. Seyden-Penne,Reductions by the Alumino- and Borohydrides in Organic Synthesis, 2^(nd)edition, Wiley-VCH, (1997); and L. Paquette, editor, Encyclopedia ofReagents for Organic Synthesis, John Wiley and Sons (1995).

In one embodiment, the present invention provides a method of making acompound of Formula I, the method comprising the step of reacting acompound 7,

wherein R¹, R², R³ and R⁴ are as defined herein and X is a halogen, witha boronic acid having a general formula

wherein A¹, A², A³, A⁴ and R⁵ are as defined herein, to make a compoundof Formula I.

In another embodiment, the present invention provides a method of makinga compound of Formula I-B, the method comprising the step of reacting acompound 7-B,

wherein R¹, R², R³ and R⁴ are as defined herein and X is a halogen, witha boronic acid having a general formula

wherein R^(6a), R^(6b), and R⁵ are as defined herein, to make a compoundof Formula I-B.

In another embodiment, the present invention provides a method of makinga compound of Formula I-C, the method comprising the step of reacting acompound 7-C,

wherein R¹, R², R³ and R⁴ are as defined herein and X is a halogen, witha boronic acid having a general formula

wherein R^(6a), R^(6b), R⁷ and R⁸ are as defined herein, to make acompound of Formula I-C.

Compounds of the present invention can possess, in general, one or moreasymmetric carbon atoms and are thus capable of existing in the form ofoptical isomers including, without limitation, racemates and racemicmixtures, scalemic mixtures, single enantiomers, individualdiastereomers and diastereomeric mixtures. All such isomeric forms ofthese compounds are expressly included in the present invention. Theoptical isomers can be obtained by resolution of the racemic mixturesaccording to conventional processes, e.g., by formation ofdiastereoisomeric salts, by treatment with an optically active acid orbase. Examples of appropriate acids are tartaric, diacetyltartaric,dibenzoyltartaric, ditoluoyltartaric, and camphorsulfonic acid and thenseparation of the mixture of diastereoisomers by crystallizationfollowed by liberation of the optically active bases from these salts. Adifferent process for separation of optical isomers involves the use ofa chiral chromatography column optimally chosen to maximize theseparation of the enantiomers. Still another available method involvessynthesis of covalent diastereoisomeric molecules by reacting compoundsof the invention with an optically pure acid in an activated form or anoptically pure isocyanate. The synthesized diastereoisomers can beseparated by conventional means such as chromatography, distillation,crystallization or sublimation, and then hydrolyzed to deliver theenantiomerically pure compound. The optically active compounds of theinvention can likewise be obtained by using optically active startingmaterials. These isomers may be in the form of a free acid, a free base,an ester or a salt.

The compounds of this invention may also be represented in multipletautomeric forms. The invention expressly includes all tautomeric formsof the compounds described herein.

The compounds may also occur in cis- or trans- or E- or Z-double bondisomeric forms. All such isomeric forms of such compounds are expresslyincluded in the present invention. All crystal forms of the compoundsdescribed herein are expressly included in the present invention.

Substituents on ring moieties (e.g., phenyl, thienyl, etc.) may beattached to specific atoms, whereby they are intended to be fixed tothat atom, or they may be drawn unattached to a specific atom, wherebythey are intended to be attached at any available atom that is notalready substituted by an atom other than H (hydrogen).

BIOLOGICAL EVALUATION

The compounds of the invention may be modified by appending appropriatefunctionalities to enhance selective biological properties. Suchmodifications are known in the art and include those which increasebiological penetration into a given biological compartment (e.g., blood,lymphatic system, central nervous system), increase oralbioavailability, increase solubility to allow administration byinjection, alter metabolism and alter rate of excretion. By way ofexample, a compound of the invention may be modified to incorporate ahydrophobic group or “greasy” moiety in an attempt to enhance thepassage of the compound through a hydrophobic membrane, such as a cellwall.

Although the pharmacological properties of the compounds of theinvention (Formulas I, I-B and I-C) vary with structural change, ingeneral, activity possessed by compounds of Formulas I and II may bedemonstrated both in vitro as well as in vivo. Particularly, thepharmacological properties of the compounds of this invention may beconfirmed by a number of pharmacological in vitro assays, as well asin-vivo animal models.

The following assays were used to characterize the ability of compoundsof the invention to modulate the activity of human p38 enzyme, inhibitthe production of TNF-α and interleukin cytokines, including IL-1,IL-1-β, IL-6 and IL-8 and/or evaluate efficacy of a compound in an invivo animal model. Another assay, a cyclooxygenase enzyme (COX-1 andCOX-2) inhibition activity in vitro assay, can be used to characterizethe ability of compounds of the invention to inhibit COX-1 and/or COX-2.

Purified and Activated Recombinant Human p38α AssayKinase Reaction Buffer: Kinase reaction buffer for p38α HTRF assaysconsists of 50 mM Tris-pH 7.5, 5 mM MgCl₂, 0.1 mg/mL BSA, 100 μM Na₃VO₄and 0.5 mM DTT.HTRF Detection Buffer: HTRF detection buffer contains 100 mM HEPES-pH7.5, 100 mM NaCl, 0.1% BSA, 0.05% Tween-20, and 10 mM EDTA.Serial Dilution of Compounds: Compounds were dissolved in 100% DMSO andserially diluted (3 fold, 10 point) in a polypropylene 96-wellmicrotiter plate (drug plate). The final starting concentration ofcompounds in the p38α enzymatic assays was 1 μM. Columns 6 and 12 (HIcontrols and LO controls respectively) in the drug plate were reservedas controls and contained only DMSO.Kinase Reaction The p38α kinase reactions were carried out in apolypropylene 96-well black round bottom assay plate in total volume of30 μL kinase reaction buffer. Appropriate concentration of purified andactivated enzyme (recombinant human) was mixed with indicatedconcentration of ATP and 100 nM GST-ATF2-Avitag, in the presence orabsence (HI control) of Compound. See table below for actualconcentrations. In the absence of substrate, the background was measuredas LO control. The reaction was allowed to incubate for 1 hour at RT.Assay Reagent Concentrations: The final reagent concentrations were 1 nMp38α and 50 μM ATP. The Km for ATP of the enzyme was 103 μM, giving aratio of ATP concentration to Km of 0.49.HTRF Detection: The kinase reaction was terminated and phospho-ATF2 wasrevealed by addition of 30 μL of HTRF detection buffer supplemented with0.1 nM Eu-anti-pTP and 4 nM SA-APC. After 60 minutes incubation at roomtemperature, the assay plate was read in a Discovery Plate Reader. Thewells were excited with coherent 320 nm light and the ratio of delayed(50 ms post excitation) emissions at 620 nM (native europiumfluorescence) and 665 nm (europium fluorescence transferred toallophycocyanin—an index of substrate phosphorylation) was determined(Park et al, 1999).Data Analysis: The proportion of substrate phosphorylated in the kinasereaction in the presence of compound compared with that phosphorylatedin the presence of DMSO vehicle alone (HI control) was calculated usingthe formula: % control (POC)=(compound−average LO)/(average HI−averageLO)*100. Data (consisting of POC and inhibitor concentration in 1M) wasfitted to a 4-parameter equation (y=A+((B−A)/(1+((x/C)̂D))), where A isthe minimum y (POC) value, B is the maximum y (POC), C is the x(compound concentration) at the point of inflection and D is the slopefactor, using a Levenburg-Marquardt non-linear regression algorithm.

The inhibition constant (Ki) of the inhibitor was estimated from theIC₅₀ (compound concentration at the point of inflection C) using theCheng-Prussof equation: Ki=IC₅₀/(1+S/Km), where S is the ATP substrateconcentration, and Km is the Michaelis constant for ATP as determinedexperimentally. All results were expressed as the mean±the standarderror of the mean. Data acquisition and non-linear regression algorithmswere performed using Activity Base v5.2 and XL-fit software v4.1respectively. All data was archived using Activity Base v5.2 software.Data for Exemplary compounds in the human p38-alpha enzyme assay isprovided in Tables 1 and 2. Examples 1-3, 6-15, 18-28, 31-32, 34-35, 37,44-46 and 51-53 exhibited IC₅₀ values of less than or equal to 100 nM.

Lipopolysaccharide-Activated PBMC Cytokine Production Assay Isolation ofPBMC

Test compounds were evaluated in vitro for the ability to inhibit theproduction of IL-1β, IL-6, and TNF-α by PBMC activated with bacteriallipopolysaccharide (LPS). Fresh leukocytes were obtained from a localblood bank, and peripheral blood mononuclear cells (PBMCs) were isolatedby density gradient centrifugation on Ficol-Paque Plus (Pharmacia).

Preparation of Test Compound Stock Solutions

All reagents were prepared in RPMI 1640+10% v/v human ABserum+1×Pens/Strep/Glu (assay medium). Test compounds were dissolved in100% DMSO and serially diluted in 96-well polypropylene round bottommicro titer plates (drug plate). Serial dilutions were then diluted1:250 into assay medium to a 4× working concentration. Compound serialdilutions were half-log, 10 point titrations with a final startingconcentration of 1 μM.

Treatment of Cells with Test Compounds and Activation withLipopolysaccharide

LPS was prepared to a 4× concentration in assay medium. 100 μl of PBMC(1×10⁶ cells/ml) were plated in a 96-well polystyrene flat bottom microtiter tissue culture plate and incubated with 50 μl of 4× compoundserial dilution for 1 hour at 37° C., 5% CO₂ in a tissue cultureincubator. 50 μl 4×LPS or control was added and the plates wereincubated at 37° C., 5% CO₂ in a tissue culture incubator for 18 hours.The final DMSO concentration was 0.1%. The total volume was 200 μL. Thefinal LPS concentration was 100 ng/mL. After 18 hours culturesupernatants were removed and IL-1β, IL-6, and TNF-α presence in thesupernatants was quantified using MSD ECL based technology.

Cytokine Measurements 20 μL of culture supernatant were added to MSDplates, and incubated for one hour at room temperature. 20 μL ofdetection antibody diluted in antibody diluent (1 μg/mL), and 110 μL of2× Read Buffer P was added, and incubated for one hour at RT.Electrochemiluminescence was measured using the SECTOR HTS Imager (MSD,Gaithersburg, Md.).

Data Analysis

Compound IC₅₀ values were calculated as follows: The proportion ofcytokine production in the presence of compound compared to the cytokineproduction in the presence of the DMSO vehicle alone (Hi control) wascalculated using the formula: Percent Control (POC)=(compound−averageLo)/(average Hi−average Lo)*100. To derive IC₅₀ values, POC was plottedagainst the Log of compound concentration (μM) and fitted to a4-parameter equation (y=A+((B−A)/(1+((x/C)̂D))), where A is the minimum y(POC) value, B is the maximum y (POC), C is the concentration ofcompound at the inflection point, and D is the slope factor, using aLevenburg-Marquardt non-linear regression algorithm. Data acquisitionand non-linear regression were performed using Activity Base and XL-fitrespectively. The compounds of Examples 2, 3, 7, 8, 12, 13, 20, 27, 31and 44 exhibited activities in the whole blood PMBC assay with IC₅₀values of equal to 125 nM or less.

Compounds of the invention can also be shown to inhibit LPS-inducedrelease of IL-1β, IL-6 and/or IL-8 from PBMC by measuring concentrationsof IL-1, IL-6 and/or IL-8 by methods well known to those skilled in theart. In a similar manner to the above described assay involving the LPSinduced release of TNF-α from PBMC, compounds of this invention can alsobe shown to inhibit LPS induced release of IL-1β, IL-6 and/or IL-8 fromPBMC by measuring concentrations of IL-1β, IL-6 and/or IL-8 by methodswell known to those skilled in the art. Thus, the compounds of theinvention may lower elevated levels of TNF-α, IL-1, IL-6, and IL-8levels. Reducing elevated levels of these inflammatory cytokines tobasal levels or below is favorable in controlling, slowing progression,and alleviating many disease states. All of the compounds are useful inthe methods of treating disease states in which TNF-α, IL-1β, IL-6, andIL-8 play a role to the full extent of the definition of TNF-α-mediateddiseases described herein.

Lipopolysaccharide-Activated THP1 Cell TNF Production Assay

THP1 cells were resuspended in fresh THP1 media (RPMI 1640, 10%heat-inactivated FBS, 1×PGS, 1×NEAA, plus 30 μM βME) at a concentrationof 1.5×10⁶ cells per mL. One hundred microliters of cells per well wereplated in a polystyrene 96-well tissue culture plate. 1.5 micrograms permL of bacterial LPS was prepared in THP1 media and transferred to thefirst 11 columns of a 96-well polypropylene plate. Column 12 containedonly THP1 media for the LO control. Compounds were dissolved in 100%DMSO and serially diluted 3 fold in a polypropylene 96-well microtiterplate (drug plate). Columns 6 and 12 were reserved as controls (HIcontrols and LO controls respectively) and contained only DMSO. 10 μL ofLPS followed by one microliter of inhibitor compound from the drug platewas transferred to the cell plate. The treated cells were induced tosynthesize and secrete TNF-α in a 37° C. humidified incubator with 5%CO₂ for 3 hours. Fifty microliters of conditioned media was transferredto a 96-well MULTI-ARRAY™ 96-well small spot plate—custom coated withMAB610 containing 100 μL of 2× Read Buffer P supplemented with 0.34 nMAF210NA polyclonal Ab labeled with ruthenium (MSD-Sulfo-TAG™-NHS ester).After an overnight incubation at room temperature with shaking, thereaction was read on the Sector Imager™ 6000. A low voltage was appliedto the ruthenylated TNF-α immune complexes, which in the presence of TPA(the active component in the ECL reaction buffer, Read Buffer P),resulted in a cyclical redox reaction generating light at 620 nm. Theamount of secreted TNF-α in the presence of AMG compounds compared withthat in the presence of DMSO vehicle alone (HI control) was calculatedusing the formula: % control (POC)=(cpd−average LO)/(averageHI−averageLO)*100. Data (consisting of POC and inhibitor concentrationin μM) was fitted to a 4-parameter equation (y=A+((B−A)/(1+((x/C)̂D))),where A is the minimum y (POC) value, B is the maximum y (POC), C is thex (cpd concentration) at the point of inflection and D is the slopefactor) using a Levenburg-Marquardt non-linear regression algorithm. Thecompounds of Examples 1-3, 6-32, 34-37, 39, 41-42, 44-46, 48 and 51-53exhibited activities in the THP-1 cellular TNF production assay withIC₅₀ values of 175 nM or less. A majority of these exemplary compoundsexhibited IC₅₀ values of 50 nM or less.

Inhibition of TNF-α Induced IL-8 in 50% Human Whole Blood

Test compounds were evaluated in vitro for the ability to inhibit theproduction of secreted IL-8 by whole blood activated with TNF-α. Freshhuman whole blood was obtained from healthy, non-medicated volunteers insodium heparin tubes.

Compound Dilution—Assay Procedure

Test compounds are serially diluted 1:3 in DMSO and then diluted 1:250into R10 (RPMI 1640, 10% human serum AB; 1×pen/strep/glutamine) to the4× working concentration to be used in the assay. 100 ul heparinizedwhole blood is plated into wells of 96 well flat bottom plates. 50 ul ofeither 4× compound or DMSO control (Final DMSO concentration is 0.1%)are added to the appropriate wells. Plates are incubated for 1 hour at37 degrees Celsius. 50 ul of 4×TNF-α (4 mM TNF-α, for a finalconcentration of 1 nM) or control (media alone) is added to theappropriate wells (Total volume=200 ul). Plates are incubated overnight(16-18 hours). 100 ul of supernatant is collected and stored in 96-wellround bottom polypropylene plates at −80 degrees Celsius or assayedimmediately for IL-8.

Cytokine Measurement

Cytokines are measured on antibody (Ab) sandwich ECL based 96-welldetection plates. 20 ul of supernatant are added to plate and plate issealed and shaken at RT for 1 hour. 130 ul of detection Ab cocktail isadded and plates are sealed and shaken for 1 hour in the dark at RT.Plates are read on MSD Sector HTS instrument. Data are analyzed and IC₅₀values generated using Activity Base and XI-fit programs. Data forexemplary compounds in the human p38-alpha enzyme assay is provided inTables 1 and 2. Examples 1-3, 6-32, 34-35, 39, 44, 46 and 52-53exhibited IC₅₀ values of less than or equal to 100 nM.

Inhibition of LPS-Induced TNF-α Production Rats

LPS was diluted in PBS (100 μg per rat). Rats (n=6) were pretreated withvehicle or compound (0.03, 0.1, 0.3 and 1.0 mg/kg, PO) 60 minutes priorto the injection of LPS (100 μg per rat/IV, tail vein). Blood washarvested via decapitation 90 minutes following the administration ofLPS. Blood was centrifuged at 12,000 rpm for 12 minutes to obtainplasma. Plasma samples were stored at −80° C. TNF-α levels weredetermined by ELISA for treatment groups that received LPS. Rat TNF-αlevels were analyzed using rat TNF-α CytoSet kit from BiosourceInternational. ELISA was completed according to the manufacturer'sinstructions. The concentration of TNF-α was interpolated fromabsorbance using the standard curve generated. For each individualsample, the TNF value from the dilution series that fell in the mostlinear portion of the standard curve was chosen and used for dataanalysis. The limit of quantitation of the ELISA was 1,000 pg/mL.

Compounds of the invention may be shown to have anti-inflammatoryproperties in animal models of inflammation, including carageenan pawedema, collagen induced arthritis and adjuvant arthritis, such as thecarageenan paw edema model (C. A. Winter et al., Proc. Soc. Exp. Biol.Med., 111:544 (1962); K. F. Swingle, in R. A. Scherrer and M. W.Whitehouse, Eds., Anti-inflammatory Agents, Chemistry and Pharmacology,13(II):33, Academic, New York (1974) and collagen induced arthritis (D.E. Trentham et al., J. Exp. Med., 146:857 (1977); J. S. Courtenay,Nature (New Biol.), 283:666 (1980)).

Collagen-Induced Arthritis (CIA) Model in Rats

Porcine type II collagen (10 mg) was dissolved in 0.1N acetic acid (5mL) two days prior to use on a rotating plate in the refrigerator.Subsequently, collagen was emulsified 1:1 with Freund's incompleteadjuvant using an emulsification needle and glass syringes yielding afinal concentration of 1 mg/mL.

Disease was induced in each animal by intradermal injection ofemulsified collagen in IFA at 10 different sites (100 μL per site) overthe back. The clinical onset of arthritis varied between days 10 to 12as indicated by hind paw swelling and ambulatory difficulties. At onset(defined as Day 0), rats were randomized to treatment groups and therapywas initiated with drug or vehicle control as noted in table above. Ratswere treated for 7 days and were sacrificed on Day 8. Paw swelling andother measurements of efficacy is described Schett et al (Schett et al.Arthritis and Rheum. 52:1604 (2005). Compound examples 7, 13, 20 and 44exhibited ED₅₀'s of 0.01, 0.02, 0.1 and 0.07 mg/kg, respectively, in therat CIA model.

Cyclooxygenase Enzyme Activity Assay

The human monocytic leukemia cell line, THP-1, differentiated byexposure to phorbol esters expresses only COX-1; the human osteosarcomacell line 143B expresses predominantly-COX-2. THP-1 cells are routinelycultured in RPMI complete media supplemented with 10% FBS and humanosteosarcoma cells (HOSC) are cultured in minimal essential mediasupplemented with 10% fetal bovine serum (MEM-10% FBS); all cellincubations are at 37° C. in a humidified environment containing 5% CO₂.

COX-1 Assay

In preparation for the COX-1 assay, THP-1 cells are grown to confluency,split 1:3 into RPMI containing 2% FBS and 10 mM phorbol 12-myristate13-acetate (TPA), and incubated for 48 h on a shaker to preventattachment. Cells are pelleted and resuspended in Hank's Buffered Saline(HBS) at a concentration of 2.5×10⁶ cells/mL and plated in 96-wellculture plates at a density of 5×10⁵ cells/mL. Test compounds arediluted in HBS and added to the desired final concentration and thecells are incubated for an additional 4 hours. Arachidonic acid is addedto a final concentration of 30 mM, the cells incubated for 20 minutes at37° C., and enzyme activity determined as described below.

COX-2 Assay

For the COX-2 assay, subconfluent HOSC are trypsinized and resuspendedat 3×10⁶ cells/mL in MEM-FBS containing 1 ng human IL-1b/mL, plated in96-well tissue culture plates at a density of 3×10⁴ cells per well,incubated on a shaker for 1 hour to evenly distribute cells, followed byan additional 2 hour static incubation to allow attachment. The media isthen replaced with MEM containing 2% FBS (MEM-2% FBS) and 1 ng humanIL-1b/mL, and the cells incubated for 18-22 h. Following replacement ofmedia with 190 mL MEM, 10 mL of test compound diluted in HBS is added toachieve the desired concentration and the cells incubated for 4 h. Thesupernatants are removed and replaced with MEM containing 30 mMarachidonic acid, the cells incubated for 20 minutes at 37° C., andenzyme activity determined as described below.

COX Activity Determined

After incubation with arachidonic acid, the reactions are stopped by theaddition of 1N HCl, followed by neutralization with 1 N NaOH andcentrifugation to pellet cell debris. Cyclooxygenase enzyme activity inboth HOSC and THP-1 cell supernatants is determined by measuring theconcentration of PGE₂ using a commercially available ELISA (Neogen#404110). A standard curve of PGE₂ is used for calibration, andcommercially available COX-1 and COX-2 inhibitors are included asstandard controls. Various compounds of the invention may be shown toinhibit the COX-1 and/or COX-2 activity.

Indications

Accordingly, compounds of the invention are useful for, but not limitedto, the prevention or treatment of inflammation, pro-inflammatorycytokines levels including, without limitation, TNF, IL-1, IL-2, IL-6and/or IL-8, and disease associated therewith. The compounds of theinvention have p38 kinase modulatory activity. In one embodiment of theinvention, there is provided a method of treating a disorder related tothe activity of p38 enzyme in a subject, the method comprisingadministering to the subject an effective dosage amount of a compound ofa compound of Formulas I, I-B or I-C.

Accordingly, the compounds of the invention would be useful in therapyas anti-inflammatory agents in treating inflammation, or to minimizedeleterious effects of p38. Based on the ability to modulatepro-inflammatory cytokine production, the compounds of the invention arealso useful in treatment and therapy of cytokine-mediated diseases.

Particularly, these compounds can be used for the treatment ofrheumatoid arthritis, Pagets disease, osteoporosis, multiple myeloma,uveitis, acute or chronic myelogenous leukemia, pancreatic β celldestruction, osteoarthritis, rheumatoid spondylitis, gouty arthritis,inflammatory bowel disease, adult restpiratory distress syndrome (ARDSpsoriasis, Crohn's disease, allergic rhinitis, ulcerative colitis,anaphylaxis, contact dermatitis, asthma, muscle degeneration, cachexia,Reiter's syndrome, type I diabetes, type II diabetes, bone resorptiondiseases, graft vs. host reaction, Alzheimer's disease, stroke,myocardial infarction, ischemia reperfusion injury, atherosclerosis,brain trauma, multiple sclerosis, cerebral malaria, sepsis, septicshock, toxic shock syndrome, fever, myalgias due to HIV-1, HIV-2, HIV-3,cytomegalovirus (CMV), influenza, adenovirus, the herpes viruses orherpes zoster infection, or any combination thereof, in a subject.

An example of an inflammation related disorder is (a) synovialinflammation, for example, synovitis, including any of the particularforms of synovitis, in particular bursal synovitis and purulentsynovitis, as far as it is not crystal-induced. Such synovialinflammation may for example, be consequential to or associated withdisease, e.g. arthritis, e.g. osteoarthritis, rheumatoid arthritis orarthritis deformans. The present invention is further applicable to thesystemic treatment of inflammation, e.g. inflammatory diseases orconditions, of the joints or locomotor apparatus in the region of thetendon insertions and tendon sheaths. Such inflammation may be, forexample, consequential to or associated with disease or further (in abroader sense of the invention) with surgical intervention, including,in particular conditions such as insertion endopathy, myofascialesyndrome and tendomyosis. The present invention is further applicable tothe treatment of inflammation, e.g. inflammatory disease or condition,of connective tissues including dermatomyositis and myositis.

The compounds of the invention can also be used as active agents againstsuch disease states as arthritis, atherosclerosis, psoriasis,hemangiomas, myocardial angiogenesis, coronary and cerebral collaterals,ischemic limb angiogenesis, wound healing, peptic ulcer Helicobacterrelated diseases, fractures, cat scratch fever, rubeosis, neovascularglaucoma and retinopathies such as those associated with diabeticretinopathy or macular degeneration.

The compounds of the invention are also useful in the treatment ofdiabetic conditions such as diabetic retinopathy and microangiopathy.

The compounds of the present invention are also useful for treatingankylosing spondylitis, inflammatory bowel disease, inflammatory pain,ulcerative colitis, Crohn's disease, asthma, chronic obstructivepulmonary disease, myelodysplastic syndrome, endotoxic shock, chronichepatitis C or a combination thereof.

Thus, the present invention provides methods for the treatment of p38protein kinase-associated disorders, comprising the step ofadministering to a subject, including human subjects, prophylacticallyor therapeutically, at least one compound of the Formula I or of FormulaII in an amount effective therefore. Other therapeutic agents such asthose described below may be employed with the inventive compounds inthe present methods. In the methods of the present invention, such othertherapeutic agent(s) may be administered prior to, simultaneously withor following the administration of the compound(s) of the presentinvention. The present invention also provides for a method for treatingatopic dermatitis by administration of a therapeutically effectiveamount of a compound of the present invention to a patient, whether ornot in need of such treatment.

In yet another embodiment, the compounds are useful for decreasing thelevel of, or lowering plasma concentrations of one or more of TNF-α,IL-1β, IL-6 and IL-8 in a subject, including human subjects, generally amammal and typically a human.

In yet another embodiment, the compounds are useful for treating a paindisorder in a subject, including human subjects, by administering to thesubject an effective dosage amount of a compound according to formulasI, I-B or I-C.

In yet another embodiment, the compounds are useful for treatingdiabetes in a subject, including human subjects, by administering to thesubject an effective dosage amount of a compound according to formulasI, I-B or I-C, to produce a glucagon antagonist effect.

In yet another embodiment, the compounds are useful for decreasingprostaglandin production in a subject, including human subjects, byadministering to the subject an effective dosage amount of a compoundaccording to formulas I, I-B or I-C.

In yet another embodiment, the compounds are useful for decreasingcyclooxygenase enzyme activity in a subject, including human subjects,by administering to the subject an effective amount of a compoundaccording to formulas I, I-B or I-C.

In yet another embodiment, the cyclooxygenase enzyme is COX-2.

Besides being useful for human treatment, these compounds are useful forveterinary treatment of companion animals, exotic animals and farmanimals, including mammals, rodents, and the like. For example, animalsincluding horses, dogs, and cats may be treated with compounds providedby the invention.

Formulations and Method of Use

Treatment of diseases and disorders herein is intended to also includetherapeutic administration of a compound of the invention, apharmaceutical salt thereof, or a pharmaceutical composition of eitherto a subject (i.e., an animal, preferably a mammal, most preferably ahuman) which may be in need of preventative treatment, such as, forexample, for pain, inflammation and the like. Treatment also encompassesprophylactic administration of a compound of the invention, apharmaceutical salt thereof, or a pharmaceutical composition of eitherto a subject (i.e., an animal, preferably a mammal, most preferably ahuman). Generally, the subject is initially diagnosed by a licensedphysician and/or authorized medical practitioner, and a regimen forprophylactic and/or therapeutic treatment via administration of thecompound(s) or compositions of the invention is suggested, recommendedor prescribed.

The amount of compound(s) which is/are administered and the dosageregimen for treating TNF-α, IL-1, IL-6, and IL-8 mediated diseases,cancer, and/or hyperglycemia with the compounds and/or compositions ofthis invention depends on a variety of factors, including the age,weight, sex and medical condition of the subject, the type of disease,the severity of the disease, the route and frequency of administration,and the particular compound employed. Thus, the dosage regimen may varywidely, but can be determined routinely using standard methods. A dailydose of about 0.001 mg/kg to 500 mg/kg, advantageously between about0.005 and about 50 mg/kg, more advantageously about 0.005 and about 30mg/kg, even more advantageously between about 0.005 and about 10 mg/kg,and even more advantageously about 0.01 and about 5 mg/kg, and should beuseful for all methods of use disclosed herein. The daily dose can beadministered in one to four doses per day.

While it may be possible to administer a compound alone, the compound ofFormulas I, I-B or I-C is normally administered as an activepharmaceutical ingredient (API) in a composition comprising othersuitable and pharmaceutically acceptable excipients. This admixture istypically referred to as a pharmaceutical composition. This compositionshould be pharmaceutically acceptable. In another embodiment, theinvention provides a pharmaceutical composition comprising a compound ofthe present invention in combination with a pharmaceutically acceptableexcipient. Pharmaceutical excipients generally include diluents,carriers, adjuvants and the like (collectively referred to herein as“excipient” materials) as described herein, and, if desired, otheractive ingredients. A pharmaceutical composition of the invention maycomprise an effective amount of a compound of the invention or aneffective dosage amount of a compound of the invention. An effectiveamount of the compound is typically that amount capable of bring about adesired physiological effect in the subject. An effective dosage amountof a compound of the invention may constitute administering to thesubject one or more than one individual dosage units of thepharmaceutically acceptable composition comprising said compound. Forexample, where two or more unit dosages of a pharmaceutical composition,such as a tablet, pill, capsule, liquid, suspension and the like, may berequired to administer an effective amount of the compound, then theeffective dosage amount of the API is less than the effective amount ofthe API. Thus, an effective dosage amount may include an amount lessthan, equal to or greater than an effective amount of the compound. Asuitable pharmaceutically acceptable composition, such as a powder, aliquid and the like, may exist in which the effective amount of thecompound is administered by administering a portion of the compositionand requiring the subject to take multiple doses over a specified periodof time.

The compound(s) of the present invention may be administered by anysuitable route, preferably in the form of a pharmaceutical compositionadapted to such a route, and in a dose effective for the treatmentintended. The compounds and compositions of the present invention may,for example, be administered orally, mucosally, topically, rectally,pulmonarily such as by inhalation spray, or parentally includingintravascularly, intravenously, intraperitoneally, subcutaneously,intramuscularly intrasternally and infusion techniques, in dosage unitformulations containing conventional pharmaceutically acceptablecarriers, adjuvants, and vehicles.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are tablets or capsules. For example, these maycontain an amount of API from about 1 to 2000 mg, advantageously fromabout 1 to 500 mg, and typically from about 5 to 150 mg. A suitabledaily dose for a human or other mammal may vary widely depending on thecondition of the patient and other factors, but, once again, can bedetermined using routine methods and practices.

For therapeutic purposes, the compounds of this invention are ordinarilycombined with one or more adjuvants or “excipients” appropriate to theindicated route of administration. If orally administered on a per dosebasis, the compounds may be admixed with lactose, sucrose, starchpowder, cellulose esters of alkanoic acids, cellulose alkyl esters,talc, stearic acid, magnesium stearate, magnesium oxide, sodium andcalcium salts of phosphoric and sulfuric acids, gelatin, acacia gum,sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, to formthe final formulation. For example, the compound(s) and excipient(s) maybe tableted or encapsulated by known and accepted methods for convenientadministration. Examples of suitable formulations include, withoutlimitation, pills, tablets, soft and hard-shell gel capsules, troches,orally-dissolvable forms and delayed or controlled-release formulationsthereof. Particularly, capsule or tablet formulations may contain one ormore controlled-release agents, such as hydroxypropylmethyl cellulose,as a dispersion with the active compound(s).

In the case of psoriasis and other skin conditions, it may be preferableto apply a topical preparation of compounds of this invention to theaffected area two to four times a day. Formulations suitable for topicaladministration include liquid or semi-liquid preparations suitable forpenetration through the skin (e.g., liniments, lotions, ointments,creams, pastes, suspensions and the like) and drops suitable foradministration to the eye, ear, or nose. A suitable topical dose ofactive ingredient of a compound of the invention is 0.1 mg to 150 mgadministered one to four, preferably one or two times daily. For topicaladministration, the active ingredient may comprise from 0.001% to 10%w/w, e.g., from 1% to 2% by weight of the formulation, although it maycomprise as much as 10% w/w, but preferably not more than 5% w/w, andmore preferably from 0.1% to 1% of the formulation.

When formulated in an ointment, the active ingredients may be employedwith either paraffinic or a water-miscible ointment base. Alternatively,the APIs may be formulated in a cream with an oil-in-water cream base.If desired, the aqueous phase of the cream base may include, for exampleat least 30% w/w of a polyhydric alcohol such as propylene glycol,butane-1,3-diol, mannitol, sorbitol, glycerol, polyethylene glycol andmixtures thereof. The topical formulation may desirably include acompound, which enhances absorption or penetration of the activeingredient through the skin or other affected areas. Examples of suchdermal penetration enhancers include DMSO and related analogs.

The compounds of this invention can also be administered by transdermaldevice. Preferably transdermal administration will be accomplished usinga patch either of the reservoir and porous membrane type or of a solidmatrix variety. In either case, the active agent is deliveredcontinuously from the reservoir or microcapsules through a membrane intothe active agent permeable adhesive, which is in contact with the skinor mucosa of the recipient. If the active agent is absorbed through theskin, a controlled and predetermined flow of the active agent isadministered to the recipient. In the case of microcapsules, theencapsulating agent may also function as the membrane.

The oily phase of the emulsions of this invention may be constitutedfrom known ingredients in a known manner. While the phase may comprisemerely an emulsifier, it may comprise a mixture of at least oneemulsifier with a fat or an oil or with both a fat and an oil.Preferably, a hydrophilic emulsifier is included together with alipophilic emulsifier, which acts as a stabilizer. It is also preferredto include both an oil and a fat. Together, the emulsifier(s) with orwithout stabilizer(s) make-up the so-called emulsifying wax, and the waxtogether with the oil and fat make up the so-called emulsifying ointmentbase, which forms the oily dispersed phase of the cream formulations.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the present invention include, for example, Tween 60, Span 80,cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodiumlauryl sulfate, glyceryl distearate alone or with a wax, or othermaterials well known in the art.

The choice of suitable oils or fats for the formulation is based onachieving the desired cosmetic properties, since the solubility of theactive compound in most oils likely to be used in pharmaceuticalemulsion formulations is very low. Thus, the cream should preferably bea non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono- or dibasic alkyl esters such as di-isoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters may be used.These may be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils can be used.

Formulations for parenteral administration may be in the form of aqueousor non-aqueous isotonic sterile injection solutions or suspensions.These solutions and suspensions may be prepared from sterile powders orgranules using one or more of the carriers or diluents mentioned for usein the formulations for oral administration or by using other suitabledispersing or wetting agents and suspending agents. The compounds may bedissolved in water, polyethylene-glycol, propylene glycol, ethanol,cormoil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodiumchloride, tragacanth gum, and/or various buffers. Other adjuvants andmodes of administration are well and widely known in the pharmaceuticalart. The active ingredient may also be administered by injection as acomposition with suitable carriers including saline, dextrose, or water,or with cyclodextrin (ie. Captisol), cosolvent solubilization (ie.propylene glycol) or micellar solubilization (ie. Tween 80).

The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution, and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employed,including synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The API may also be administered by injection as a composition withsuitable carriers including saline, dextrose, or water. The dailyparenteral dosage regimen will be from about 0.1 to about 30 mg/kg oftotal body weight, preferably from about 0.1 to about 10 mg/kg, and morepreferably from about 0.25 mg to 1 mg/kg.

For pulmonary administration, the pharmaceutical composition may beadministered in the form of an aerosol or with an inhaler including drypowder aerosol.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable non-irritating excipient such as cocoabutter and polyethylene glycols that are solid at ordinary temperaturesbut liquid at the rectal temperature and will therefore melt in therectum and release the drug.

The pharmaceutical compositions may be subjected to conventionalpharmaceutical operations such as sterilization and/or may containconventional adjuvants, such as preservatives, stabilizers, wettingagents, emulsifiers, buffers etc. Tablets and pills can additionally beprepared with enteric coatings. Such compositions may also compriseadjuvants, such as wetting, sweetening, flavoring, and perfuming agents.

Accordingly, in yet another embodiment, the present invention providesthe use of a medicament for the treatment of inflammatory conditions,including RA, psoriasis, psoriatic arthritis, pain, COPD, Crohnsdisease, and other indications described herein.

In yet another embodiment, there is provided a method of manufacturing amedicament for the treatment of inflammation, the method comprisingcombining an amount of a compound according to Formulas I, I-B or I-Cwith a pharmaceutically acceptable carrier to manufacture themedicament.

Combinations

While the compounds of the invention can be dosed or administered as thesole active pharmaceutical agent, they can also be used in combinationwith one or more compounds of the invention or in conjunction with otheragents. When administered as a combination, the therapeutic agents canbe formulated as separate compositions that are administeredsimultaneously or sequentially at different times, or the therapeuticagents can be given as a single composition.

The phrase “co-therapy” (or “combination-therapy”), in defining use of acompound of the present invention and another pharmaceutical agent, isintended to embrace administration of each agent in a sequential mannerin a regimen that will provide beneficial effects of the drugcombination, and is intended as well to embrace co-administration ofthese agents in a substantially simultaneous manner, such as in a singlecapsule having a fixed ratio of these active agents or in multiple,separate capsules for each agent.

Specifically, the administration of compounds of the present inventionmay be in conjunction with additional therapies known to those skilledin the art in the prevention or treatment of TNF-α, IL-1, IL-6, and IL-8mediated diseases, cancer, and/or hyperglycemia.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the accepted dosage ranges. Compoundsof Formulas I, I-B or I-C may also be administered sequentially withknown anti-inflammatory agents when a combination formulation isinappropriate. The invention is not limited in the sequence ofadministration; compounds of the invention may be administered eitherprior to, simultaneous with or after administration of the knownanti-inflammatory agent.

The compounds of the invention may also be used in co-therapies withanti-neoplastic agents such as other kinase inhibitors, including CDKinhibitors, TNF inhibitors, metallomatrix proteases inhibitors (MMP),COX-2 inhibitors including celecoxib, rofecoxib, parecoxib, valdecoxib,and etoricoxib, NSAID's, SOD mimics or a_(v)β₃ inhibitors.

The foregoing description is merely illustrative of the invention and isnot intended to limit the invention to the disclosed compounds,compositions and methods. Variations and changes, which are obvious toone skilled in the art, are intended to be within the scope and natureof the invention, as defined in the appended claims. From the foregoingdescription, one skilled in the art can easily ascertain the essentialcharacteristics of this invention, and without departing from the spiritand scope thereof, can make various changes and modifications of theinvention to adapt it to various usages and conditions. All patents andother publications recited herein are hereby incorporated by referencein their entireties.

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein each of A¹, A²,A³ and A⁴, independently, is CR⁶ or N, provided that no more than two ofA¹, A², A³ and A⁴ is N; B is O, S or N—CN; R¹ is H, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl or C₃₋₁₀-cycloalkyl, each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl andC₄₋₁₀-cycloalkenyl optionally comprising 1-4 heteroatoms selected fromN, O and S and optionally substituted with one or more substituents ofR⁹, or R¹ is a 3-8 membered monocyclic or 6-12 membered bicyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, saidheteroatoms selected from O, N, or S, wherein said ring system isoptionally substituted independently with one or more substituents ofR⁹; each of R² and R³, independently, is H, halo, haloalkyl, NO₂, CN,OR⁷, SR⁷, NR⁷R⁷, NR⁷R⁸, C(O)R⁷, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl or C₃₋₁₀-cycloalkyl, each of the C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl and C₄₋₁₀-cycloalkenyloptionally comprising 1-4 heteroatoms selected from N, O and S andoptionally substituted with one or more substituents of R⁹; R⁴ is CN,C(O)R⁷, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl or C₃₋₈-cycloalkyl,each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl andC₃₋₈-cycloalkyl optionally comprising 1-4 heteroatoms selected from N, Oand S and optionally substituted with one or more substituents of R⁹; R⁵is R⁷, NR⁷R⁷, NR⁷R⁸, OR⁷, SR⁷, OR⁸, SR⁸, C(O)R⁷, C(NCN)R⁷, C(O)R⁸,C(NCN)R⁸, C(O)C(O)R⁷, OC(O)R⁷, COOR⁷, C(O)C(O)R⁸, OC(O)R⁸, COOR⁸,C(O)NR⁷R⁷, C(O)NR⁷R⁸, OC(O)NR⁷R⁸, NR⁷C(O)R⁷, NR⁷C(O)R⁸, NR⁷C(O)NR⁷R⁷,NR⁷C(O)NR⁷R⁸, NR⁷(COOR⁸), NR⁷(COOR⁸), S(O)₂R⁷, S(O)R⁸, S(O)₂NR⁷R⁷,S(O)₂NR⁷R⁸, NR⁷S(O)₂NR⁷R⁸, NR⁷S(O)₂R⁷ or NR⁷S(O)₂R⁸; each R⁶,independently, is H, halo, haloalkyl, NO₂, CN, OR⁷, NR⁷R⁷ orC₁₋₁₀-alkyl, the C₁₋₁₀-alkyl optionally comprising 1-4 heteroatomsselected from N, O and S and optionally substituted with one or moresubstituents of R⁹; each R⁷, independently, is H, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl or C₄₋₁₀-cycloalkenyl,each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyland C₄₋₁₀-cycloalkenyl optionally comprising 14 heteroatoms selectedfrom N, O and S and optionally substituted with one or more substituentsof NR⁸R⁹, NR⁹R⁹, OR⁸, SR⁸, OR⁹, SR⁹, C(O)R⁸, OC(O)R⁸, COOR⁸, C(O)R⁹,OC(O)R⁹, COOR⁹, C(O)NR⁸R⁹, C(O)NR⁹R⁹, NR⁹C(O)R⁸, NR⁹C(O)R⁹,NR⁹C(O)NR⁸R⁹, NR⁹C(O)NR⁹R⁹, NR⁹(COOR⁸), NR⁹(COOR⁹), OC(O)NR⁸R⁹,OC(O)NR⁹R⁹, S(O)₂R⁸, S(O)₂NR⁸R⁹, S(O)₂R⁹, S(O)₂NR⁹R⁹, NR⁹S(O)₂NR⁸R⁹,NR⁹S(O)₂NR⁹R⁹, NR⁹S(O)₂R⁸, NR⁹S(O)₂R⁹, R⁸ or R⁹; R⁸ is a partially orfully saturated or fully unsaturated 3-8 membered monocyclic, 6-12membered bicyclic, or 7-14 membered tricyclic ring system, said ringsystem formed of carbon atoms optionally including 1-3 heteroatoms ifmonocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms iftricyclic, said heteroatoms selected from O, N, or S, and wherein eachring of said ring system is optionally substituted independently with1-5 substituents of R⁹, oxo, NR⁹R⁹, OR⁹, SR⁹, C(O)R⁹, COOR⁹, C(O)NR⁹R⁹,NR⁹C(O)R⁹, NR⁹C(O)NR⁹R⁹, OC(O)NR⁹R⁹, S(O)₂R⁹, S(O)₂NR⁹R⁹, NR⁹S(O)₂R⁹, ora partially or fully saturated or unsaturated 5-6 membered ring ofcarbon atoms optionally including 1-3 heteroatoms selected from O, N, orS, and optionally substituted independently with 1-3 substituents of R⁹;alternatively, R⁷ and R⁸ taken together form a saturated or partially orfully unsaturated 5-6 membered monocyclic or 7-10 membered bicyclic ringof carbon atoms optionally including 1-3 heteroatoms selected from O, N,or S, and the ring optionally substituted independently with 1-5substituents of R⁹; and R⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂,acetyl, oxo, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl or a saturated orpartially or fully unsaturated 5-8 membered monocyclic, 6-12 memberedbicyclic, or 7-14 membered tricyclic ring system, said ring systemformed of carbon atoms optionally including 1-3 heteroatoms ifmonocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms iftricyclic, said heteroatoms selected from O, N, or S, wherein each ofthe C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and each ring of said ring system isoptionally substituted independently with 1-3 substituents of halo,haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl, ethoxyl,propyl, propoxyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl,methylamine, dimethylamine, ethylamine, diethylamine, propylamine,isopropylamine, dipropylamine, diisopropylamine, benzyl or phenyl. 2.The compound of claim 1, or a pharmaceutically acceptable salt thereof,wherein one of A¹, A², A³ and A⁴, independently, is N and the remainingof A¹, A², A³ and A⁴, independently, is CR⁶ wherein each R⁶,independently, is H, F, Cl, Br, CF₃, —OCF₃, C₂F₅, —OC₂F₅, —O—C₁₋₄-alkyl,—C₁₋₄-alkyl-O—C₁₋₆-alkyl, —S—C, 6-alkyl, —C₁₋₄-alkyl-S—C₁₋₆-alkyl,—NH—C₁₋₆-alkyl, —N(C₁₋₆-alkyl)₂, —C₁₋₄-alkyl-NH—C₁₋₆-alkyl,—C₁₋₃-alkyl-N(C₁₋₄-alkyl)₂, NO₂, NH₂, CN, C₁₋₁₀-alkyl, the C₁₋₁₀-alkyloptionally substituted with one or more substituents of R⁹.
 3. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein each of A¹, A², A³ and A⁴, independently, is CR⁵ wherein eachR⁶, independently, is H, F, Cl, Br, CF₃, —OCF₃, C₂F₅, —OC₂F₅,—O—C₁₋₆-alkyl, —C₁₋₄-alkyl-O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl,—C₁₋₄-alkyl-S—C₁₋₆-alkyl; —NH—C₁₋₆-alkyl, —N(C₁₋₆-alkyl)₂,—C₁₋₄-alkyl-NH—C₁₋₆-alkyl, C₁₋₃-alkyl-N(C₁₋₄-alkyl)₂, NO₂, NH₂, CN,C₁₋₁₀-alkyl, the C₁₋₁₀-alkyl optionally substituted with one or moresubstituents of R⁹; and each of R² and A³, independently, is H or halo.4. The compound of claim 3, or a pharmaceutically acceptable saltthereof, wherein R¹ is C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl orC₃₋₁₀-cycloalkyl, each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl and C₄₋₁₀-cycloalkenyl optionally comprising 1-4heteroatoms selected from N, O and S and optionally substituted with oneor more substituents of R⁹.
 5. The compound of claim 3, or apharmaceutically acceptable salt thereof, wherein R¹ is phenyl,naphthyl, pyridyl, pyrimidyl, triazinyl, pyridazinyl, pyrazinyl,quinolinyl, isoquinolinyl, quinazolinyl, isoquinazolinyl, thiophenyl,furyl, tetrahydrofuryl, pyrrolyl, tetrahydropyrrolyl, pyrazolyl,imidazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, oxazolinyl,isoxazolyl, isoxazolinyl, oxadiazolyl, isothiazolyl, indolyl, indolinyl,isoindolyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl,benzisoxazolyl, benzopyrazolyl, benzothiazolyl, benzimidazolyl,piperidinyl, pyranyl, cyclopropyl, cyclobutyl or cyclohexyl, each ofwhich is optionally substituted as defined in claim
 1. 6. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, wherein eachof R² and R³, independently, is H, halo, haloalkyl, NO₂, CN, OR⁷, NR⁷R⁷or C₁₋₁₀-alkyl.
 7. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R⁴ is CN, C(O)R⁷, C₁₋₄-alkylC(O)R⁷,methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl,tert-butyl, pentyl, neopentyl or C₁₋₄-alkyl-amino-C₁₋₄-alkyl orC₁₋₁₀-dialkylaminoC₁₋₄-alkyl-.
 8. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R⁵ is NR⁷R⁷, NR⁷R⁸,C(O)R⁷, C(O)R⁸, C(O)NR⁷R⁷, C(O)NR⁷R⁸, NR⁷C(O)R⁷, NR⁷C(O)R⁸,NR⁷C(O)NR⁷R⁷, NR⁷C(O)NR⁷R⁸, NR⁷(COOR⁷), NR⁸(COOR⁷), S(O)₂R⁷, S(O)₂R⁸,S(O)₂NR⁷R⁷, S(O)₂NR⁷R⁸, NR⁷S(O)₂NR⁷R⁸, NR⁷S(O)₂R⁷ or NR⁷S(O)₂R⁸.
 9. Thecompound of claim 8, or a pharmaceutically acceptable salt thereof,wherein R⁸ is a ring selected from phenyl, naphthyl, pyridyl, pyrimidyl,triazinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl,quinazolinyl, isoquinazolinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl,imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl,indolyl, isoindolyl, benzofuranyl, benzothiophenyl, benzimidazolyl,benzoxazolyl, benzisoxazolyl, benzopyrazolyl, benzothiazolyl,tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl,wherein said ring is optionally substituted independently with 1-3substituents of R⁹.
 10. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein B is O; R¹ is phenyl, naphthyl,pyridyl, pyrimidyl, triazinyl, pyridazinyl, pyrazinyl, quinolinyl,isoquinolinyl, quinazolinyl, isoquinazolinyl, thiophenyl, furyl,tetrahydrofuryl, pyrrolyl, tetrahydropyrrolyl, pyrazolyl, imidazolyl,triazolyl, tetrazolyl, thiazolyl, oxazolyl, oxazolinyl, isoxazolyl,isoxazolinyl, oxadiazolyl, isothiazolyl, indolyl, indolinyl, isoindolyl,benzofuranyl, dihydrobenzofuranyl, benzothiophenyl, benzisoxazolyl,benzopyrazolyl, benzothiazolyl, benzimidazolyl, piperidinyl, pyranyl,cyclopropyl, cyclobutyl or cyclohexyl, each of which is optionallysubstituted independently with 1-3 substituents of R⁹; each of R² andR³, independently, is H, halo, haloalkyl or C₁₋₁₀-alkyl; R⁴ is CN,C(O)R⁷, C₁₋₄-alkylC(O)R⁷, methyl, ethyl, propyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, pentyl, neopentyl orC₁₋₄-alkyl-amino-C₁₋₄-alkyl or C₁₋₁₀-dialkylaminoC₁₋₄-alkyl-; R⁵ isNR⁷R⁷, NR⁷R⁸, C(O)NR⁷R⁷, C(O)NR⁷R⁸, NR⁷C(O)R⁷, NR⁷C(O)R⁸, NR⁷C(O)NR⁷R⁷,NR⁷C(O)NR⁷R⁸, NR⁷(COOR⁷), NR⁷(COOR⁸), S(O)₂R⁷, S(O)₂R⁸, S(O)₂NR⁷R⁷,S(O)₂NR⁷R⁸, NR⁷S(O)₂NR⁷R⁸, NR⁷S(O)₂R⁷ or NR⁷S(O)₂R⁸; each R⁶,independently, is H, F, Cl, Br, CF₃, —OCF₃, C₂F₅, —OC₂F₅, —O—C₁₋₆-alkyl,—C₁₋₄-alkyl-O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl, —C₁₋₄-alkyl-S—C₁₋₆-alkyl,—NH—C₁₋₄-alkyl, —N(C₁₋₆-alkyl)₂, —C₁₋₄-alkyl-NH—C₁₋₆-alkyl,—C₁₋₃-alkyl-N(C₁₋₄-alkyl)₂, NO₂, NH₂, CN or C₁₋₁₀-alkyl, the C₁₋₁₀-alkyloptionally substituted with one or more substituents of R⁹; each R⁷,independently, is H, C₁₋₁₀-alkyl or C₃₋₁₀-cycloalkyl, wherein theC₁₋₁₀-alkyl and C₃₋₁₀-cycloalkyl optionally comprising 1-4 heteroatomsselected from N, O and S and optionally substituted with 1-3substituents of R⁹; R⁸ is a ring selected from phenyl, naphthyl,pyridyl, pyrimidyl, triazinyl, pyridazinyl, pyrazinyl, quinolinyl,isoquinolinyl, quinazolinyl, isoquinazolinyl, thiophenyl, furyl,pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl,isoxazolyl, isothiazolyl, indolyl, isoindolyl, benzofuranyl,benzothiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl,benzopyrazolyl, benzothiazolyl, tetrahydrofuranyl, pyrrolidinyl,oxazolinyl, isoxazolinyl, thiazolinyl, pyrazolinyl, morpholinyl,piperidinyl, piperazinyl, pyranyl, dioxozinyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl, wherein said ring is optionallysubstituted independently with 1-3 substituents of R⁹; and R⁹ is H,halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, oxo, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxylor a saturated or partially or fully unsaturated 5-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S,wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and each ring ofsaid ring system is optionally substituted independently with 1-3substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl.
 11. The compound of claim 1, or apharmaceutically acceptable salt thereof, selected from:N-cyclopropyl-3-(7-ethyl-1-(2-fluorophenyl)-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-5-fluoro-4-methylbenzamide;N-cyclopropyl-3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-5-fluoro-4-methylbenzamide;N-cyclopropyl-3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylbenzamide;3-(1-(2-chlorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-cyclopropyl-5-fluoro-4-methylbenzamide;N-cyclopropyl-3-fluoro-5-(1-(2-fluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylbenzamide;3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methyl-N-(1-methyl-1H-pyrazol-5-yl)benzamide;N-cyclopropyl-3-(1-(2,4-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-5-fluoro-4-methylbenzamide;3-(1-(2-chlorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-cyclopropyl-4-methylbenzamide;N-cyclopropyl-3-(1-(2,4-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylbenzamide;N-cyclopropyl-4-methyl-3-(7-methyl-1-(2-methylphenyl)-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)benzamide;N-cyclopropyl-3-fluoro-4-methyl-5-(7-methyl-1-(2-methylphenyl)-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)benzamide;N-(3-(1-(2,4-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylphenyl)cyclopropanecarboxamide;N-cyclopropyl-3-fluoro-4-methyl-5-(7-methyl-1-(1-methylethyl)-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)benzamide;3-(1,2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-3-isoxazolyl-4-methylbenzamide;3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-5-fluoro-N-3-isoxazolyl-4-methylbenzamide;N-cyclopropyl-4-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-5-methyl-2-pyridinecarboxamide;4-chloro-N-cyclopropyl-3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)benzamide;3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-5-fluoro-4-methyl-N-(1-methylethyl)benzamide;3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-5-fluoro-N,4-dimethylbenzamide;N-cyclopropyl-3-(1-(2,5-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-5-fluoro-4-methylbenzamide;N-cyclopropyl-3-(1-(2,5-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylbenzamide;3-(1-(2,5-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methyl-N-(1-methylcyclopropyl)benzamide;3-(1-(2,5-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-3-isoxazolyl-4-methylbenzamide;3-(1-(2,4-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-3-isoxazolyl-4-methylbenzamide;3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methyl-N-1,3-thiazol-2-ylbenzamide;4-chloro-N-cyclopropyl-3-(1-(2,5-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)benzamide;3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methyl-N-(1-methylcyclopropyl)benzamide;3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-5-fluoro-4-methylbenzamide;3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylbenzamide;3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methyl-N-2-methyloxy)-5-(trifluoromethyl)phenyl)benzamide;N-cyclopropyl-3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-(hydroxymethyl)benzamide;N-cyclopropyl-3-(1-(2,4-difluorophenyl)-7-ethyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylbenzamide;N-cyclopropyl-3-(1-(2,6-difluorophenyl)-7-methyl-6-thioxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylbenzamide;N-cyclopropyl-3-(1-(2,4-difluorophenyl)-7-(2,3-dihydroxypropyl)-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylbenzamide;N-cyclopropyl-3-(1-(4-fluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylbenzamide;4-chloro-N-cyclopropyl-3-(1-(4-fluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)benzamide;and1-cyclopropyl-3-(3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylphenyl)urea.12. A pharmaceutical composition comprising a compound according toclaim 1 and a pharmaceutically acceptable excipient.
 13. Apharmaceutical composition comprising a compound according to claim 11and a pharmaceutically acceptable excipient.
 14. A method of treatinginflammation in a subject, the method comprising administering to thesubject a compound of claim
 11. 15. A method of treating rheumatoidarthritis in a subject, the method comprising administering to thesubject a compound of claim
 11. 16. A method of treating rheumatoidarthritis in a subject, the method comprising administering to thesubject the pharmaceutical composition of claim
 13. 17. A method oftreating Pagets disease, osteoporosis, multiple myeloma, uveitis, acuteor chronic myelogenous leukemia, pancreatic β cell destruction,osteoarthritis, rheumatoid spondylitis, gouty arthritis, adultrespiratory distress syndrome (ARDS), Crohn's disease, allergicrhinitis, anaphylaxis, contact dermatitis, asthma, muscle degeneration,cachexia, Reiter's syndrome, type I diabetes, type II diabetes, boneresorption diseases, graft vs. host reaction, Alzheimer's disease,stroke, myocardial infarction, ischemia reperfusion injury,atherosclerosis, brain trauma, multiple sclerosis, cerebral malaria,sepsis, septic shock, toxic shock syndrome, fever, myalgias due toHIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza, adenovirus, theherpes viruses or herpes zoster infection or a combination thereof in asubject, the method comprising administering to the subject a compoundof claim
 11. 18. A method of lowering plasma concentrations of TNF-a,IL-1, IL-6, IL-8 or a combination thereof in a subject, the methodcomprising administering to the subject a compound of claim
 11. 19. Amethod of treating psoriasis, psoriatic arthritis or a combinationthereof in a subject, the method comprising administering to the subjecta compound of claim
 11. 20. A method of treating ankylosing spondylitis,inflammatory bowel disease (IBD), inflammatory pain, ulcerative colitis,Crohn's disease, asthma, chronic obstructive pulmonary disease (COPD),myelodisplastic syndrome, endotoxic shock or a combination thereof in asubject, the method comprising administering to the subject a compoundof claim
 11. 21. A method of preparing a compound according to claim 1,the method comprising the step of reacting a compound 7,

wherein R¹, R², R³ and R⁴ are as defined in claim 1 and X is a halogen,with a boronic acid having a general formula

wherein A¹, A², A³, A⁴ and R⁵ is as defined in claim 1, to make acompound of claim 1.